Funded Projects
Division of Pharmaceutical Outcomes and Policy
Non-Invasive Technology to Continuously Monitor and Improve Patient Medication Adherence
Ingestible sensors and smart pills hold the potential to revolutionize how we measure and monitor patient medication adherence; however, the impact of these technologies has been limited by low patient acceptability and high costs. Our goal is to develop a new non-invasive technology that is low cost, acceptable to patients, and provides patients with personalized adherence information.
Division of Chemical Biology and Medicinal Chemistry
Large-Scale Polypharmacology Modeling Using Deep Learning
We will explore deep learning methods for polypharmacological modeling to accelerate drug repositioning in different therapeutic areas. Prediction of off-target toxicities with such models can help to reduce the number of drug failures. Analysis of our models will help us to understand the structure-activity profiles as well as relationships between chemical structure and biological function.
Division of Molecular Pharmaceutics
Cytotoxic Stem Cell Therapy for Pediatric Brain Cancer
Medulloblastoma (MBM) is the most common brain cancer in children. We will develop a game-changing approach to MBM therapy where tumor-homing neural stem cells seek out invasive MBM cells and deliver anti-cancer gene products to eradicate local and invasive tumor foci. This innovative therapy will address an enormous medical need and move MBM treatment in exciting new directions.
Division of Chemical Biology and Medicinal Chemistry
Profiling Cellular Phosphoinositide Metabolism for Disease Diagnosis
Phosphoinositides (PIs) are a family of essential signaling molecules that regulate a wide range of cellular processes. Aberrant regulation of PI metabolism is an established hallmark for many diseases. We propose a novel fluorous approach that will enable the systematic profiling of PI metabolism in live cells, which can serve as a diagnostic tool for diseases.
Robert Hughes
Division of Chemical Biology and Medicinal Chemistry
Optogenetics, Cytoskeletal Dysregulation, and Disease
We are developing a suite of light-activated, protein-based switches that enable the manipulation of cytoskeletal dynamics at will in living cells. These switches may enable us to rescue, rejuvenate, or otherwise prolong the livelihoods of diseased cells and tissues in a wide variety of disease states in a tightly controlled, non-invasive manner.
Division of Molecular Pharmaceutics
Carolina Nanoformulation Workshop
The Carolina Nanoformulation Workshop (CNW) is an innovative, state-of-the-art didactic-cum-practical training workshop at UNC-Chapel Hill that addresses key drug delivery issues relevant to both industrial and academic scientists. CNW develops a strong comprehensive educational resource, and fosters potential academia-industry partnerships to stimulate entrepreneurial development.
Division of Molecular Pharmaceutics
RECOPE: Reverse Conceptual Product Engineering
RECOPE is a comprehensive developmental and educational methodology to facilitate pharmaceutical research translation from bench to bedside and increase clinical relevance in academia for faculty and staff. RECOPE will plug into scientific, educational, and commercialization resources and expertise at UNC and RTP to maximize the impact on the entrepreneurial development, research and education.
Center for Integrative Chemical Biology and Drug Discovery
Molecular Simulations of Ultra-Large Biological Systems
Our ultimate goal is to build a computer system that can reproduce the inner workings of a cell. Such a system will be a major research tool in drug discovery and molecular biology. The objective of this project is to develop a pilot software and perform a proof-of-concept study. The innovation of our approach involves the creation of synergy between the scientific disciplines of molecular dynamics and systems biology.
Division of Molecular Pharmaceutics
Shoebox-Sized Plasmapheresis Machine for Cheap & Rapid Generation of Convalescent Serum in Africa
Current healthcare infrastructure in third world, resource-limited settings do not allow for preparation of convalescent serum, an important toolset needed in our fight against emerging infectious diseases. We seek to combine the latest in water sanitation technologies to enable rapid and cheap preparation of convalescent serum.
Division of Chemical Biology and Medicinal Chemistry
Decipher a Highly Specific Biomarker for Targeted Treatment of Pancreatic Cancer
Pancreatic ductal adenocarcinoma (PDAC) is among the most aggressive and dismal of all human cancers, often carrying a very poor prognosis and horrendous survival rate. One of the major challenges in developing precision medicine against PDAC is the lack of biomarkers that are highly specific to PDAC. The results from this project will greatly facilitate the early diagnosis and targeted treatment of PDAC.
Division of Pharmacotherapy and Experimental Therapeutics
Solving the Mystery of Highly Variable Drug Disposition in Pregnant Women: Are Unique Hepatic Drug Metabolizing Enzymes Activated During Pregnancy?
This project will ignite new opportunities for research in the field of clinical pharmacology in special populations. We will accomplish this by determining whether unique drug metabolizing enzymes are (1) activated by the dramatic sex hormone changes that occur throughout pregnancy, and (2) contribute to the unexplained variability in drug clearance and effects that occur in pregnant women.
Division of Molecular Pharmaceutics
P-Glycoprotein Targeted Antibody Conjugates for Combating Chemoresistant Tumors
P-glycoprotein (Pgp), which contributes to drug resistance in approximately half of known human cancers, remains undruggable after over 30-years of intensive research. We aim to utilize antibody conjugates to detect and treat chemoresistant cancers that overexpress Pgp. By turning Pgp into a “Trojan Horse” for targeted delivery, we may provide the first clinically effective approach to tackle Pgp-mediated drug resistance nearly 40 years after its discovery.
Division of Pharmacotherapy and Experimental Therapeutics
Enhancing Tumor Delivery of Nanoparticle Anticancer Agents Using Microbeam Radiation Therapy
The promise of nanoparticle (NP) anticancer agents remains largely unfulfilled due to low tumor delivery, in which only 10-20% of NPs are distributed to tumors. Thus, there is a strong need to discover methods that can capitalize on the promise of NPs by significantly and safely enhancing tumor delivery. We will evaluate if novel microbeam radiation therapy (MRT) significantly enhances NPs delivery to tumors with minimum toxicity to normal tissue.
Center for Integrative Chemical Biology and Drug Discovery
Controlling the Mucus That Kills Pulmonary Patients
50 million Americans suffer from asthma, chronic obstructive pulmonary disease, and cystic fibrosis. A hallmark of these diseases is excessive mucus that can lead to airway plugging. Current therapies are not effective in reducing airway mucus. Our work will lay the foundation for developing novel inhibitors of a protein whose role in airway mucus overproduction was recently discovered at UNC.
Division of Molecular Pharmaceutics
Carolina E(I) Lab: A Multidisciplinary, Entrepreneurial Experience in Transforming Bold Ideas Into Successful Ventures
To develop future leaders in pharma/biotech R&D, we must fuse classical graduate student/postdoc (GS+P) education with experience and training in innovation, multidisciplinary teamwork and entrepreneurship. The E(I) Lab is an 8-month program bringing GS+P from diverse disciplines across UNC to conceive and execute innovative solutions to unmet needs in healthcare.
Division of Practice Advancement and Clinical Education
Transforming Data Into Knowledge: Fostering Institutional Effectiveness Through Real-Time Analytics
As higher education becomes increasingly data rich, we must demonstrate achievement of institutional initiatives in new and innovative ways. We propose a state-of-the-art data analytics system that provides decision support across the School and Eshelman Institute for Innovation. This system will advance our efforts to institutionalize assessment and accelerate change in knowledge management.
Division of Molecular Pharmaceutics
Transdifferentiation: A Novel Approach to Personalized Cancer Therapy
Our multi-disciplinary team will create a disruptive advancement in the treatment of aggressive brain cancer. We will use next-generation technology to convert the skin of cancer patients into novel personalized tumor-homing neural stem cell therapies (iNSCs). We will then test multiple aspects of iNSC therapy using our unique pre-clinical models that closely mirror clinical cancer treatment.
Division of Molecular Pharmaceutics
Priming the Liver to Resist Cancer Metastasis
We will formulate a nanoparticle for the delivery of plasmid DNA to the liver resulting in the local expression of an engineered CXCL12-trap protein. Chemokine, CXCL12, is a key factor in the metastasis of colorectal cancer cells, as well as the recruitment of immunosuppressive cells. This formulation almost completely resolved any occurrence of colorectal liver metastasis. No metastasis in any other organs was found.
Division of Molecular Pharmaceutics
Engineered Antibodies With Carefully Tuned Mucin-Affinity for Enhanced Mucosal Protection
All exposed organs not covered by skin are coated with a mucus layer; these mucosal surfaces are prime sites for infectious disease transmission. Building off of our pioneering discovery that antibodies can interact with mucins to trap pathogens, we are focusing on engineering novel antibody constructs that possess even greater ‘muco-trapping’ potency for protection against mucosal infections.
Division of Chemical Biology and Medicinal Chemistry
Light-Triggered Launching of Anti-Glioblastoma Therapeutics From Cellular Silos
We will explore the preparation and properties of neural stem cell-conveyed phototherapeutics and the wavelength-programmed release of drugs (1) in well-defined 2D co-cultures with target cells, (2) to target cells in 3D culture, and (3) to glioblastoma sites in animal models.
Division of Chemical Biology and Medicinal Chemistry
Developing Carbohydrate-Based Medicines
Carbohydrates play essential functions in regulating various physiological and pathological processes. Advanced methods in designing and synthesizing carbohydrate molecules will open a new path for drug discovery for cancer, cardiovascular diseases and microbial infections. Three projects are proposed to improve the pharmacology of heparin, a carbohydrate-based drug for anticoagulant therapy.
Division of Practice Advancement and Clinical Education
Innovations in Practice Transformation: Advancing Medication Optimization in Primary Care
We are engaged in research to create best practices in optimizing medication use to influence new value-based payment and care delivery models and improve patient care. Through this award, we will address an unmet need by creating innovative technologies to facilitate the assimilation and dissemination of best practices throughout the country. These technologies will be key to accelerating the adoption and scale of new approaches to optimizing medication use.
Division of Chemical Biology and Medicinal Chemistry
Center for Innovation in Pharmacy Simulation (CIPS)
The Center for Innovation in Pharmacy Simulations will develop a state-of-the-art, data-driven technology platform in support of all major missions of the School. We will develop simulation tools based on serious gaming concepts to enhance all phases of education, both professional and graduate, and pharmaceutical research including medication discovery, delivery, optimization, assessment, and practice.
Structural Genomics Consortium – UNC
The SGC-UNC: A Center for Open and Collaborative Target Discovery
The SGC-UNC promotes innovation through open sharing of research, material, and data. Greater than 80% of the enzymes known as protein kinases are understudied and their role in human biology is poorly understood. We aim to generate a functional map of these kinases to guide discovery of new medicines, through the creation and study of small molecules (called chemical probes) in a wide range of human diseases.
Division of Molecular Pharmaceutics
Long Acting Formulations for HIV Therapy
This project proposes chemistry for the sustained release of ART therapy for the treatment of HIV/AIDS. Using chemical modifications, we aim to create a pro-drug that can then be formulated for long-acting release of therapeutic drug. Also these proposed methods keep in mind inexpensive scalable production of the formulation.
Center for Nanotechnology in Drug Delivery
Engineering 3D Models of Cancer Metastasis with Pro-Inflammatory Microenvironment for Cancer Immunotherapy
Three-dimensional in vitro models fill the gap between cell cultures and whole-animal systems. We aim to engineer ex vivo cancer metastases with pro-inflammatory microenvironment in these 3D models, and utilize them to develop cancer immunotherapy. We propose a revolutionary approach for cancer treatment by using the patient’s white blood cells, engineered to target and kill cancer metastases.
Division of Chemical Biology and Medicinal Chemistry
Evolving ‘Unnatural’ Natural Products to Target Orphan GPCRs
Our ultimate goal is to build synthetic microorganisms that invent new drugs. We will harness natural biosynthetic chemistry for targeted evolution of new therapeutics against pharmacologically important GPCRs. This work will contribute to broadly applicable and transformative technologies for completely cell-based high-throughput screening for drug development.
Division of Chemical Biology and Medicinal Chemistry
Novel Strategy for Prevention and Overcoming Multidrug Resistant Cancer by Small Molecule
Multidrug resistance in cancer is often correlated with the overexpression of P-glycoprotein (P-gp), a major ATP-dependent drug efflux pump. We plan to target ectopically expressed intracellular P-gp in MDR cancer by using novel small molecules, which selectively induce apoptosis only in MDR cancer. We will demonstrate a novel therapeutic strategy for overcoming the cancer MDR phenotype.
Division of Molecular Pharmaceutics
Hijacking Vaccines: Durable Immunity Via Genetic Editing of B Cells by CRISPR/Cas9
Achieving protective levels of antibodies in the peripheral circulation is crucial to effective defense against many infectious diseases; unfortunately, this has proven to be exceedingly challenging for many pathogens. Here, we propose a vaccination strategy that harnesses the latest advances in genomic engineering to bypass current limitations of vaccines and passive immunization strategies.
Division of Chemical Biology and Medicinal Chemistry
Proteasome Sensors as Potential Biomarkers for Neurodegenerative Diseases
Neurodegenerative diseases such as Alzheimer’s and Parkinson’s are estimated to affect six million Americans and cost the U.S. over $800 billion each year. Early diagnosis and treatment are essential if we want to stop the progression of these debilitating diseases. We believe that the decreased activity of the proteasome can be used as a biomarker before clinical symptoms occur.
Division of Pharmacotherapy and Experimental Therapeutics
Clinical Implementation of Pharmacogenomics: The Actionable Genome
The goal of this project is to provide a direct path to the clinical implementation of pharmacogenomics (PGx). That is, we will develop a novel test that assesses genetic information on 18 genes, which we call the actionable genome. If we know the genetic information from these genes we can more precisely prescribe and dose multiple drugs. This should be the new standard for personalized medicine.
Division of Chemical Biology and Medicinal Chemistry
Develop Novel Natural Product Inspired Library of Multi-Target Compounds for Anticancer Drug Discovery
To take full advantage of the unique skeleton of natural product (NP) and the enormous data generated in current drug research, we will integrate polypharmacophores or privileged fragments from drugs or ligands of current top anticancer drug targets into three types of NP. The multi-target leads so discovered should hold great promise for developing new anticancer drugs with excellent efficacy.
Division of Molecular Pharmaceutics
Fabrication of Innovative Intravaginal Rings by State-of-the-Art 3D Printing Technology
Women account for more than half of all people living with HIV and over 2,800 women a day are infected with HIV. Our goal is to develop a female-controlled method for prevention using intravaginal rings. Using a state-of-the-art engineering process we will fabricate IVRs in a way that cannot be achieved with conventional engineering, i.e. injection molding and hot-melt extrusion.
Division of Chemical Biology and Medicinal Chemistry
Development of Chemical Heterochromatin Inhibitors as Novel Epigenetic Cancer Therapies
Disruption of core epigenetic pathways underpins a large swath of human cancers. Heterochromatin gene repression has been found at fault in a growing number of human tumors including that of the breast, prostate, pancreas and liver. Here we advance first in class inhibitors of heterochromatin gene repression discovered at UNC and examine their clinical potential using multiple human cancer models.
Division of Molecular Pharmaceutics
Engineered Bispecific Fusion Proteins (BFP) for Targeted Delivery of Therapeutic Nanoparticles and Viral Vectors
Specific delivery of a therapeutic payload to target cells remains a major bottleneck in enhancing efficacy and reducing side effects of many particle-based therapies, including both synthetic nanoparticles and viral vectors. Here, we propose engineering bispecific fusion proteins that can broadly facilitate targeting of particles to diverse cells with molecular specificity.
Division of Chemical Biology and Medicinal Chemistry
Novel Single Domain Antibody Mimics for Targeted Cancer Therapy
The escape from immunosurveillance is indispensable for the initiation, progression, and metastasis of most cancers. This project focuses on developing novel targeting ligands that can be integrated with chemo/cytokine traps for precise immunotherapies against malignant tumors.
Division of Molecular Pharmaceutics
Systemic Stem Cell Therapy for Simultaneous Treatment of Breast Cancer Metastases in Multiple Organs
Thirty percent of women diagnosed with breast cancer develop metastatic disease, yet the disease remains incurable. We propose a new approach to treatment, where tumor-homing engineered stem cells are systemically infused to simultaneously eradicate the primary breast cancer lesion, extracranial metastases, and cancer metastases spread to the brain. This renews hope for a cure.
Division of Molecular Pharmaceutics
Magneto-Mechanical Cancer Nanotherapeutics
We propose a novel cancer therapy approach, in which cancer cells are destroyed without the use of chemotherapeutic drugs by mechanical motion of magnetic nanoparticles actuated remotely by applied alternating current magnetic fields of very low frequency. Such fields and treatments are safe for surrounding tissues but disrupt the cytoskeleton and kill cancer cells while leaving healthy cells intact.
Division of Chemical Biology and Medicinal Chemistry
“Clickable” Assays of Metabolic Enzymes for Precision Medicine
Endogenous small molecules, which are biosynthesized by metabolic enzymes, present an additional axis to the “central dogma” of life. The proposed work aims to develop an innovative technology platform to assay metabolic enzymes and profile endogenous small molecules at the single cell level. Such an assay and profiling, when used in a patient’s cells, would be novel tools for precision medicine.
Structural Genomics Consortium – UNC
The UNC Catalyst for Rare Disease Drug Discovery
Although mutations have been identified for thousands of monogenic rare diseases, progression of this knowledge to disease understanding and, ultimately, therapy or cure remains challenging. The UNC Catalyst for Rare Disease Drug Discovery engages rare disease foundations and innovatively addresses this gap with an open platform for generating knowledge and providing key research tool materials.
Ph.D. Candidate
Division of Chemical Biology and Medicinal Chemistry
Heparin-Like Carbohydrates for the Treatment of Acute Liver Failure
Heparin products are standard therapeutics for the prevention and treatment of coagulation disorders, yet they have various other unexploited biological roles. While the mechanism of acute liver failure (ALF) is unclear, patients may benefit from treatment with heparin or heparin-like carbohydrates. Using an APAP-overdose mouse model, heparin compounds will be used to probe the mechanism of ALF.
Ph.D. Candidate
Center for Integrative Chemical Biology and Drug Discovery
Development of MPP8 Inhibitors for HIV Latency Reversal
Current treatments for human immunodeficiency virus permit viral persistence, requiring lifelong medication. HIV latency contributes to maintaining this HIV reservoir that prevents eradication of the disease. We will develop a chemical probe to disrupt essential epigenetic processes of the latent viral state, thereby validating epigenetic intervention as a treatment strategy against HIV.
Pharm.D. Student
The Air You Breathe Campaign: A Targeted and Innovative Approach to Promoting Treatment Guidelines and Educating Practitioners
Lymphangioleiomyomatosis (LAM) is a rare disease affecting primarily women of childbearing age. An estimated 250,000 women are currently living with this disease and are undiagnosed, misdiagnosed and untreated. The Air You Breathe Campaign is a practice model to promote the new LAM healthcare guidelines, educate clinicians, raise awareness and positively impact patient outcomes.
Ph.D. Candidate
Division of Chemical Biology and Medicinal Chemistry
Accelerating the Discovery of Protein-Protein Interaction Stabilizers
Protein-protein interactions (PPI) significantly outnumber single proteins – the traditional targets of drug discovery efforts. Thus, modulation of PPIs would vastly enlarge the druggable genome. Small-molecule stabilization of PPIs is an emerging but under-studied concept in drug discovery. We propose to develop in silico methodologies to accelerate the discovery of PPI stabilizers.
Postdoctoral Research Associate
Division of Chemical Biology and Medicinal Chemistry
Accurate Property Prediction for Drug Polymorphs
Current cheminformatics QSAR/QSPR models do not take polymorphs into account. In this project, we propose a new method for predicting compound properties that explicitly accounts for drug crystal structure. To achieve this objective, we combine accurate ab initio quantum-chemical calculation of crystals and co-crystals with machine learning to build a predictive model of drug properties.
Pharm.D. Student
Comparison of Induction of Vaginal Antibody Response Following Intranasal vs. Intramuscular Influenza Vaccination
Despite the success of the HPV vaccine, there is currently no approved vaccine for other common STIs in the female genital tract. We believe our human clinical study that directly compares vaginal antibody response following intranasal vs. intramuscular influenza vaccination will provide valuable insights that will guide design of future vaccines against vaginally transmitted infections.
Postoctoral Research Associate
Division of Pharmacotherapy and Experimental Therapeutics
Phenotypic Probe to Individualize the Treatment of Monoclonal Antibodies and Antibody Drug Conjugates
Compared to small-molecule drugs, monoclonal antibodies and antibody-drug conjugates are cleared via the mononuclear phagocyte system (MPS). Variability in MPS function may be responsible for the clinically relevant variability in the PK and PD of these agents. Thus, there is a need to develop methods, such as phenotypic probes of the MPS, that can be used to individualize the dose of these agents.
Postdoctoral Research Associate
Division of Chemical Biology and Medicinal Chemistry
A Facile Approach Towards Cell-Permeable and Photoactivatable Phospholipids
Phospholipids are essential signaling molecules that regulate a wide range of cellular processes. Dysregulation of phospholipid metabolism has been implicated in various diseases. Lack of cell-permeability and rapid, dynamic metabolism presents a challenging task for phospholipid studies. We propose a simple and novel methodology to enable phospholipids that are cell-permeable and photoactivatable.
Pharm.D. Student
Improving Patient Retention in Clinical Trials Through the Use of Wearable Devices
Clinical drug trials primarily rely on returned pill counts and e-diaries to assess medication compliance; however, these methods have been shown to be inaccurate and biased. Our revolutionary platform utilizes wearable devices to continuously monitor dosing events in real time. Early detection and intervention empower investigators to employ behavioral modification to improve patient retention.
Cao Carter
Division of Pharmacoengineering and Molecular Pharmaceutics
A Companion Diagnostics for Checkpoint Immunotherapy: Beyond Static Biomarkers
A companion diagnostics we are developing in this project is based on the dynamic properties of cytokine secretion by peripheral T-cells.This diagnostics would fundamentally change current time-frozen static diagnostic approaches to more dynamic characterization of immune functions and its potential responsive status to checkpoint immunotherapy.
Shawn Hingtgen
Division of Pharmacoengineering and Molecular Pharmaceutics
T-STEM: A New Approach to Cancer Therapy Through Cellular Hybrids
Cell therapies are changing the face of cancer treatment. We propose to create a cellular hybrid designed to overcome hurdles that limit effectiveness of current cell therapies. This highly novel approach promises a cell that migrates through solid tissue and co-opts the immune system for unparalleled tumor killing.
Michael Jarstfer
Division of Chemical Biology and Medicinal Chemistry
Rescuing Rare Genetic Disorders by Kinase Inhibition
Many genetic diseases result from mutations called premature termination codons, which result in expression of truncated and dysfunctional protein. In several diseases, such as cystic fibrosis and Duchenne muscular dystrophy, ~10 % of cases are caused by premature termination codons. This project will establish if the function of genes with premature termination codons can be rescued by stabilizing the mutated RNAs. If successful, this would provide a novel approach to treat genetic disorders.
Dmirtri Kireev
Division of Chemical Biology and Medicinal Chemistry
Taming Entropic Pseudo-Forces in Chemical Biology and Drug Discovery
We intend to provide medicinal chemists with new tools for a more effective drug design on challenging protein targets. Our goal is to devise an approach to design more potent and specific leads by harnessing the ligand-protein binding entropy. This goal will be achieved through an innovative blend of high-performance computing (HPC) and machine learning.
Samantha Pattenden
Division of Chemical Biology and Medicinal Chemistry
Developing Small Molecule Probes to Inhibit the Regulatory Capacity of Long Noncoding RNAs
Molecules called long noncoding RNAs (lncRNAs) finely tune the expression of genes essential for normal growth and development. Aberrant lncRNA activity drives many genetic disorders and cancers, but, currently, no approved therapies exist to target lncRNA function. We developed an assay to track lncRNA regulatory activity that we will apply to find inhibitors of two disease-causing lncRNAs.
Chunping Qiao
Division of Pharmacoengineering and Molecular Pharmaceutics
Improving AAV Production Method with CRISPR/Cas9
We will utilize the state of the art CRISPR/Cas9 genome editing technology to create a high titer adeno-associated virus (AAV) producer cell line via targeted delivery. With the successful completion of this project, our producer cell line method will revolutionize the AAV production process, generating an innovative AAV producer cell line to meet the rising demands of AAV preclinical/clinical studies.
Dmitri Kireev
Division of Chemical Biology and Medicinal Chemistry
Cracking the Key to Pluripotency through Molecular Biosystems Computing
The goal of the project is to propose and characterize a dynamic structural model of the OCT4-mediated pluripotency repression. It will be achieved through a multidisciplinary strategy, combining novel Molecular BioSystems (MB) approach with a unique Chromatin in-vivo Assay, to address a challenging question in the field of regenerative biology. Activities will include MB simulations, software development and experimental testing through real-time chromatin imaging.
Paul Watkins
Division of Pharmacotherapy and Experimental Therapeutics
An Exosome-Based Assay for Predicting Idiosyncratic Drug-Induced Liver Injury
It is not currently possible to identify drugs that cause very rare but life-threatening liver injury. As a result, the FDA may require large and long clinical trials just to assure liver safety. The objective of this project is to develop a new test of liver safety that capitalizes on our recent discoveries. If successful, this test will make new drugs available faster, more affordable, and safer.
Jeffrey Aubé
Division of Chemical Biology and Medicinal Chemistry
beta-Lactams: New Generations and New Uses
b-Lactams, such as penicillin, are among the most successful drug classes of all time. Although useful in nearly every arena of infectious disease treatment, but with one especially important exception – tuberculosis. This program supports and extends a recent discovery that a modified class of cephalosporins are active in test tube models of TB. The Aubé lab seeks to build upon this by inventing and testing several entirely new classes of b-lactams.
Kevin Frankowski
Division of Chemical Biology and Medicinal Chemistry
Inspired by Nature: Enhancing the UNC Compound Collection
Borrowing inspiration from the privileged structural motifs found in natural products and utilizing nontraditional synthetic methods for library synthesis, we aim to assemble a proprietary screening compound resource for the UNC research community. The compound set will contain natural product-inspired analogues and fragments to mirror the interactions of natural products with biological targets. Screening this diverse collection will facilitate the discovery of small molecule modulators for a broad range of novel therapeutic targets.
Shawn Hingtgen
Division of Pharmacoengineering and Molecular Pharmaceutics
Personalized Therapy for the Incurable: Metastatic Lung Cancer
Metastatic lung cancer remains one of the deadliest types of cancer. We propose a radical new therapy, where tumor-homing cell therapies target and eradicate cancer foci. This novel approach promises a powerful anti-tumor weapon for clinicians and hope for patients.
Rihe Liu
Division of Chemical Biology and Medicinal Chemistry
Biepitopic and Bispecific Chimeric Antigen Receptors for T-Cell Therapy
Chimeric Antigen Receptor (CAR)-T cell therapy is a cell-based treatment that uses engineered T cells to recognize and drastically kill cancer cells. This project is directed to address the urgent unmet need in cancer immunotherapy by developing the next generation CAR-T cells in which the CAR is capable of targeting two epitopes or two antigens with significantly reduced antigen escape.
Jacqueline McLaughlin
Division of Practice Advancement and Clinical Education
Precision Education for Clinical Decision Making
In health professions education, clinical teaching cases are critical in promoting the sophisticated clinical reasoning and decision-making skills required for success in contemporary practice. However, current methods for generating appropriately complex and relevant clinical cases – and the related questions required to assess student learning – are time- and labor-intensive. We aim to develop a dynamic, innovative system that efficiently generates precisely tailored clinical cases on demand. The proposed system will apply cutting-edge technologies to provide health sciences faculty with custom-designed just-in-time instructional and assessment resources.
Stephen Frye and Kenneth Pearce
Division of Chemical Biology and Medicinal Chemistry
Development of DNA-encoded Chemical Library Technology for Enhancement of CICBDD High Throughput Screening Capabilities
Traditional high throughput screening tests small molecules (thousands to millions) in individual wells using a biochemical or cellular assay. We propose establishing a transformational technology in the CICBDD to utilize DNA-encoded libraries (DELs) where diverse compounds (potentially >100 million) are selected as hits in binding assays versus targets of interest. Initial DELs will be designed using our unique insights into chromatin regulatory domains that modulate gene expression during development and disease.
Nate Hathaway
Division of Chemical Biology and Medicinal Chemistry
Center for Allele Specific Epigenetic Regulation (CASR)
The Center for Allele Specific Regulation (CASR) is a group formed between the divisions of CBMC and DPET. We will create innovative chemically based gene control systems and apply these tools to repress key oncogenic targets in incurable metastatic human prostate cancer. The CASR will create a new hub at the Eshelman School of Pharmacy to bring our promising new platform to labs across UNC.
Alexander Kabanov
Division of Pharmacoengineering and Molecular Pharmaceutics
Systemic Targeting of Mononuclear Phagocytes for Parkinson’s Disease Gene Therapy
We propose a novel gene therapy approach in which a therapeutic gene is first, systemically delivered to blood-borne immune cells and then, carried by these cells to the disease site. This approach allows for non-invasive, safe and efficient access to most secluded sites in the brain, where the therapeutic molecules are produced to treat Parkinson’s disease. Such therapies could improve lives of Parkinson’s and other patients suffering from incurable brain diseases.
David Lawrence
Division of Chemical Biology and Medicinal Chemistry
Optogenetic Manipulation of Striatal Neurons
Light-activatable ion channels or pumps have been encoded into neurons in order to map neural pathways. However, this technology is unable to probe the relationship between intracellular biochemistry and neuronal/animal behavior. We’ve developed a strategy to photo-activate specific proteins within specific compartments of individual neurons. The ability to control compartmentalized signaling in the brain will be used to assess the basis of addictive behavior and dysfunctional motor control.
Tim Wiltshire
Division of Pharmacotherapy and Experimental Therapeutics
Pharmacogenetic Implementation: The Actionable Genome
The goal of this proposal is to demonstrate that a preemptive pharmacogenetic testing program is cost-effective, and improve potential for prescribing of the right drug or right dose of drug. This will ultimately lead to direct improved health outcomes for patients. The comprehensive pharmacogenetic test used, DNA2Rx TM, has been developed at UNC, and covers all of the actionable gene/drug combinations. It will be implemented in cardiology, oncology, pain, transplant and psychiatry clinics.
Xiao Xiao
Division of Pharmacoengineering and Molecular Pharmaceutics
Targetable and Regulatable Gene Delivery Platform Technology for Gene Therapy
Our proposal aims to make key contributions to the next generation gene therapy technology, a platform that enables the creation of novel targetable, regulatable and invisible gene vectors. We will use forced molecular evolution and structural rational design to engineer novel adeno-associated virus (AAV) vectors for the treatment of human diseases.
Kayley Lyons
Ph.D. Candidate
Division of Practice Advancement and Clinical Education
Collabucate: Your Team’s Personal Collaboration Coach
In classrooms, professors assign group work, but simply placing students in groups does not guarantee students will learn to work as a team and it may even produce opposite effects. Collabucate is a mobile application which supports optimal student collaboration by fostering social awareness and providing teams with personalized group learning techniques.
Courtney Schaal
Ph.D. Candidate
Division of Chemical Biology and Medicinal Chemistry
Optimization of a Novel, Two-Step High Throughput Method to Assess Chromatin for Screening of Compounds that Alter Chromatin Accessibility in Cancer
Chromatin modulation has gained increasing attention for therapeutic efforts as its importance in cancer and other disease continues to be unveiled; however, no high-throughput methods to interrogate chromatin exist. This project will deliver a first-in-class, high-throughput assay for chromatin-focused drug discovery. Its application will be used to screen large compound libraries to identify “hit” compounds with therapeutic potential, it will be readily transferable to other labs, and can be applied to study basic chromatin biology.
Sherif Farag
Ph.D. Candidate
Division of Chemical Biology and Medicinal Chemistry
Re-Engineering Bacteria with NRPLinker: A Computational Approach to Designing Novel Non-Ribosomal Peptide Antibiotics
As the threat of antibiotic resistance continues to rise, the need of novel antibiotics is greater than ever. We propose the development of “NRPS-Linker” the first computational tool to guide rational design of novel NRP antibiotics. The tool explores the importance of Inter-Modular Linkers (IMLs) and their key role in coordination between modules within a non-ribosomal peptide synthetase (NRPS). NRPS-Linker will be a valuable asset for researchers interested in combinatorial biosynthesis of novel NRPs.
Jonathan Bogart
Ph.D. Candidate
Division of Chemical Biology and Medicinal Chemistry
A Chemoezymatic Platform for the Discovery of Bicycle Thiopeptide Therapeutics
Antibiotic resistance/infectious diseases are constant threats to global public health. Thiopeptides are an emerging family of macrocyclic natural products that represent a huge, untapped potential for new antibiotic scaffolds. These scaffolds remain elusive due to their structural complexity and the few, limited strategies used to access them. I propose to use a chemoenzymatic approach to access new bicyclic thiopeptide analogs and develop more clinically relevant bicyclic thiopeptide therapeutics.
Jingjing Li
Ph.D. Candidate
Division of Chemical Biology and Medicinal Chemistry
Screening of PD-1-Binding Epitopes from a PD-L1 Library for the Development of Novel PD-1 Inhibitors and Vaccines
PD-1 and PD-L1 targeting antibody-based immunotherapy that is extensively used in clinical anti-cancer therapy is costly and tends to cause toxicities and resistance. In this proposal, protein engineering combined with high throughput protein display technology will be adopted to develop peptide-based vaccines to stimulate active immune response and inhibitors to block PD-1/PD-L1 signaling, which hopefully addresses aforementioned problems.
Elena Batrakova
Division of Pharmacoengineering and Molecular Pharmaceutics
Developing Exosome-based Delivery of TPP1 for Batten Disease Therapy
We’re focused on the development of a new drug delivery system exploiting exosomes for gene and protein transfer for treatment of Batten disease. The results from mutations in the TPP1 gene that cause an insufficiency or complete lack of the soluble lysosomal enzyme tripeptidyl peptidase-1 (TPP1). We propose using exosomes released by macrophages for systemic delivery of TPP1 or TPP1-encoding genetic material to the brain. Exosomes, naturally occurring nanosized vesicles, offer distinct advantages that uniquely position them as highly effective drug carriers. This non-viral approach has no risk of long-term immunogenicity or systemic activation that is a disadvantage for viral gene delivery and other activation-based immunotherapies.
Carter Cao
Division of Pharmacoengineering and Molecular Pharmaceutics
A Novel Format of Bispecific Antibody: Unleash the Hidden Power of TNF-α Trimerization to Overcome Anti-cancer Resistance
Targeting CD20-positive B-cells with monoclonal antibodies (mAbs) has become an effective strategy in the B-cell hematologic malignancies. However, a significant number of patients remain refractory or develop resistance to anti-CD20 antibody therapy. In this project, we propose a novel format of bispecific antibody (bsAb) to leverage intrinsic TNF-α trimerization to overcome resistance to anti-CD20 antibodies.
Daniel Crona
Division of Pharmacotherapy and Experimental Therapeutics
Precision Dosing of TKIs for Real World Patients with CML
Greater diversity among real-world patients (RWPs), when compared to patients enrolled in clinical trials, can result in medication exposure-response variability. For chronic myelogenous leukemia (CML) patients, tyrosine kinase inhibitors (TKIs) are the treatment of choice. However, RWPs experience a high rate of dose interruptions/treatment discontinuations. This is the first step toward developing a precision dosing tool that seeks to maximize efficacy and adherence, and to minimize toxicities for all real-world CML patients.
Jennifer Fox
Office of Professional Education
Valuing Our People: Promoting Staff Development to Establish a Culture of Workplace Engagement
The most valuable asset of any organization is its people; however, the everyday demands of institutions often prioritize focus on outputs rather than developing human capital. Through this proposal, we intend to help the School face the challenge of identifying opportunities, developing strategic initiatives, and executing innovative programming aimed to support staff development and promote a culture of workplace engagement that aligns with the School’s mission, vision, and strategic initiatives.
Dong Fu
Division of Pharmacotherapy and Experimental Therapeutics
A Novel ‘Out-of-the-Well’ Design for Microplates to Facilitate High-Throughput Cell-based Screening in Drug Development
Collagen sandwich culture of primary hepatocytes, the most reliable in-vitro hepatocyte culture system, is the ideal system for evaluating drug metabolism and hepatotoxicity. However, it is difficult and problematic to establish collagen sandwich culture of hepatocytes in microplates for high-throughput screening. Thus, this project focuses on developing innovative and unconventional designs to establish high quality and reliable sandwich culture of hepatocytes in microplates for high-throughput cell-based screening.
Michael Jarstfer
Division of Chemical Biology and Medicinal Chemistry
Discovery of Senescence Markers and Drug Targets
There are no cures for age-related disorders, and current treatments are typically both life-long and expensive. To address this problem, we will identify new targets for drug discovery efforts towards the treatment of age-related disorders. At the cellular level, many age-related disorders result from the accumulation of senescent cells. Our work will lead to the discovery of new ways to clear senescent cells to promote the growth of healthy ones, leading to rejuvenated tissues.
Michael Jay
Division of Pharmacoengineering and Molecular Pharmaceutics
The Osmopatch: An Osmotic Controlled-Release Transdermal Drug Delivery System
Most of the new technologies for enhancing the transdermal delivery of drugs for which the diffusion through the stratum corneum is very slow to involve expensive manufacturing methods or the use of an external power source, e.g., microneedles, iontophoresis, electroporation, etc. The ‘Osmopatch’ is an innovative transdermal patch that, upon exposure to water or water vapor, can greatly increase the delivery of low-flux drugs across the skin either systemically or locally using a simple osmosis-driven process.
Alexander Kabanov
Division of Pharmacoengineering and Molecular Pharmaceutics
Optimizing miR-29 Nanoformulation for Neuroprotection
As a therapeutic strategy for Alzheimer’s disease (AD) we propose to use microRNAs called “miR-29” that improves survival of brain neurons during the disease. Our proposal is addressing a principal challenge in delivering a microRNAs to the brain by using exosomes, the natural vesicles, produced by immune cells, that are capable to carry biomolecules to the site of the disease in the brain. If successful our work would provide the foundation for future therapy for AD.
Dmitri Kireev
Division of Chemical Biology and Medicinal Chemistry
Probing the Impact of Epigenetics on Neuronal Network Dynamics and Cognition
The proposed research is directed at a better understanding of the role epigenetics plays in neuronal dynamics and cognition. The project goal is to develop a biologically meaningful model of a neuronal network (NN) with embedded epigenetic regulation. It will be achieved through (i) extending our Molecular BioSystems (MB) software to simulations of molecular events in NN, and (ii) a case study of NN dynamics in C. elegans brain.
David Lawrence
Division of Chemical Biology and Medicinal Chemistry
Assessing Laboratory Risks in an Augmented Environment
Scientific researchers are exposed to a wide variety of dangers in the laboratory. Unfortunately, emergency training exercises, particularly those within an authentic setting, are unacceptably dangerous. We seek to create a first-of-its-kind augmented reality training module designed to provide an immersive lab safety environment.
Robert McGinty
Division of Chemical Biology and Medicinal Chemistry
Orthogonal Nucleosomes to Transform Epigenetics Research
Misregulation of chromatin signaling is a hallmark of many human diseases, especially cancer.
Despite this fundamental relevance to human health, technical challenges have prevented full elucidation of how combinations of DNA and histone modifications function at an individual nucleosome. We are developing tools to understand how this complex signaling hub choreographs genome-templated processes in health and disease.
Merrie Mosedale
Division of Pharmacotherapy and Experimental Therapeutics
Development of a Novel Human In-vitro System to Predict Cholestatic Drug-induced Liver Injury
Cholestatic drug-induced liver injury (DILI) accounts for a quarter of DILI cases, is associated with significant morbidity and mortality, and is an issue of rising concern among the pharmaceutical industry and regulatory agencies. We are developing a novel human in vitro system to predict cholestatic DILI liability. Our platform will include cultured primary human cholangiocytes isolated using cutting-edge techniques and suitable for the evaluation of both drug- and bile-acid induced mechanisms of cholestatic DILI.
Samantha Pattenden
Division of Chemical Biology and Medicinal Chemistry
Development of a First-in-class High Throughput Assay Based on Chromatin Accessibility
Changes in chromatin organization are associated with many diseases. However, chromatin as a focus for therapeutic intervention remains in its infancy in part because of the limited validation of molecular targets. Thus, there is an immediate need for the creation of novel in vivo chromatin-based screening technologies. We will develop a powerful, target agnostic high throughput screening platform that measures the dynamic states of chromatin accessibility in cells using and enzyme-based approach.
Xiaodong Wang
Center for Integrative Chemical Biology and Drug Discovery
Chemical Biology Tools for High-precision Probing of Neuronal Development
Despite this fundamental relevance to human health, technical challenges have prevented full elucidation of how combinations of DNA and histone modifications function at an individual nucleosome. We are developing tools to understand how this complex signaling hub choreographs genome-templated processes in health and disease.
Kevin Frankowski
Center for Integrative Chemical Biology and Drug Discovery
Allosteric Dopamine Modulators for the Treatment of CNS Disorders
Therapeutics targeting dopamine regulation has proven to be an effective treatment strategy for myriad diseases, such as Parkinson’s disease, schizophrenia, and restless legs syndrome. Unfortunately, currently available therapeutics are often associated with highly limiting side effects, in large part due to cross-reactivity of the available drugs with other receptors. The central goal of this project is to develop allosteric dopamine modulators that would possess truly selective activity for a single dopamine receptor subtype.
Shawn Hingtgen
Division of Pharmacoengineering and Molecular Pharmaceutics
Native and Bioprinted 3D Tissue Array Platform for Predicting Cancer Metastasis and Drug Response
We propose to develop innovative micro-engineered platforms to advance multiple aspects of cancer therapy. Capitalizing on the expertise of our multi-disciplinary, we hope to improve the care for cancer patients by re-defining treatment strategies.
Frederico Innocenti
Division of Pharmacotherapy and Experimental Therapeutics
Defining the Microbiome in Colon Cancer to Achieve Precision Therapeutics
In this study, we will test the hypothesis that the tumor microbiome affects the response of colorectal cancer patients to drug therapy. Species-level quantification of tumor bacterial expression will be assessed by NanoString technology. We will use bioinformatic analysis to associate patient clinical and molecular data to microbial composition and differential immune cell infiltration in the tumor microenvironment. We expect results that will improve the precision of standard therapy for colorectal cancer patients.
Tim Wilson
Division of Chemical Biology and Medicinal Chemistry
Artificial Intelligence (AI) Driven de Novo Design of Selective Kinase Inhibitors
This project develops a novel computational drug design platform that is based on the application of Artificial Intelligence (AI) to the task of generating structurally novel compounds with optimized specificity and selectivity. Based on deep and reinforcement learning approaches, our framework integrates two deep neural networks – generative and predictive –to generate novel targeted chemical libraries. Specifically, we will focus on three kinases: Cyclin-dependent kinase 1 (CDK1), I-kappa-B kinase epsilon (IKKe), and Serine/threonine-protein kinase TBK1.
Lindsey James
Center for Integrative Chemical Biology and Drug Discovery
Transforming CRISPR-Cas9 Genome-Editing Efficiency
The CRISPR-Cas9 system is widely accepted as one of the most powerful tools for precise gene editing and has the potential to revolutionize both basic research and personalized medicine; however, its utility is limited by its low efficiency. Successful Cas9 editing is dependent on repairing DNA via a specific pathway, and we proposed to develop novel inhibitors that favor the desired DNA repair pathway to enable more efficient and precise genome editing.
Alexander Kabanov
Division of Pharmacoengineering and Molecular Pharmaceutics
Nanoparticle Delivery of Cas9 and Therapeutic gRNAs to the Brain
We are developing a therapy for Angelman syndrome, a neurodevelopmental disorder occurring due to deletion of maternal Ube3a gene. We propose to unsilence the paternal gene that is functional but epigenetically silenced. Working towards this, we are exploring a novel technology to deliver gene-editing machinery to neurons in the brain. If successful, our strategy could provide the first ever treatment, and possibly cure, for Angelman syndrome and can also be applied to autism and other neurodevelopmental disorders that currently have no cure.
Ken Pearce
Center for Integrative Chemical Biology and Drug Discovery
Pursuit of a Novel Treatment for Alzheimer’s Disease via Targeting microRNA-29 Expression
Alzheimer’s disease (AD) is an age-related neurodegenerative disease that results in progressive memory loss and dementia. Current therapies do not target the underlying pathology of AD. We have developed a novel cellular screen focused on a microRNA (miR-29) as an essential molecule in the healthy brain with considerable therapeutic potential for AD. Our ultimate aim is discovery of a new starting point for therapeutic development with a novel mechanism of action for prevention and treatment of AD.
Alexander Tropsha
Division of Chemical Biology and Medicinal Chemistry
Elucidating the Effect of Bariatric Surgery on Diabetes Progression Using Patient Data
Bariatric surgery, originally developed to treat obesity, was shown to lead to the remission of Type 2 diabetes often associated with obesity in more than 60% of the patients. Increasing evidence indicates a close relationship between the composition of intestinal microbiota and diabetes. This project investigates the link between bariatric surgery, diabetes, and microbiome to identify biomarkers responsible for such remission and enable the development of novel non-invasive therapeutic options to treat type 2 diabetes.
Jeff Aubé
Division of Chemical Biology and Medicinal Chemistry
Kappa Opioid Receptor Agonists Lacking Side Effects
Agonists of the kappa opioid receptor (KOR) are potential agents for the treatment of pain and pruritis (itch), but like drugs that act at other opioid receptors, known agents have problematic side effects. The present project is to develop new KOR agonists that lack side effects due to their ability to selectively activate a specific pathway of the KOR (a property known as ligand bias).
Division of Pharmacotherapy and Experimental Therapeutics
Precision Dosing of Direct Oral Anticoagulants
A systematic approach to dose individualization is imperative to maximize drug efficacy and safety in patients, and realize the vision of precision medicine. The direct oral anticoagulants (DOACs) are high priority candidate drugs that may benefit from development of precision dosing strategies. This project will focus on collecting opportunistic clinical data and evaluation of precision dosing strategies to facilitate dose individualization of the direct oral anticoagulants (DOACs) in diverse patient populations.
Sam Lai
Division of Pharmacoengineering and Molecular Pharmaceutics
In Vivo Engineering of T-cells for CAR-T-based Therapy
“CAR-T” is a very promising form of immunotherapy for cancer, but is currently limited by time and costs to prepare the engineered T-cells ex vivo, as well as poor efficacy against solid cancers. Here, we seek to reducing the time and costs of CAR-T therapy while minimizing T-cell exhaustion from extended cultures ex vivo by directly modifying the T-cells in vivo. If successful, we will greatly accelerate clinical adoption of CAR-T therapy as well as other adoptive cell transfer therapies.
Rihe Lui
Division of Chemical Biology and Medicinal Chemistry
A Wholly Protein-based Self-assembly Nanoplatform for Tunable Cancer Immunotherapy
Most nanoplatforms are based on inorganic or/and organic materials that have limitations in homogeneity, large scale production, and difficulty in introducing protein-based biological molecules. This project is directed at developing an innovative nanoplatform called ‘ProNano’ that is wholly composed of proteins. Biological molecules with different functions can be efficiently integrated through a facile add-mix self-assembly process. The platform is highly versatile for different cancer types and ideal for tunable combination immunotherapy.
James Beaudoin
Ph.D. Candidates
Division of Pharmacotherapy and Experimental Therapeutics
Cross-Cultural Leadership Development Committee Expansion Initiative
The Cross-Cultural Leadership Development Committee was founded in the Eshelman School of Pharmacy in 2015 with the mission to provide an opportunity for students to cultivate professional skills currently not found in the curriculum that will help them transition into an increasingly diverse workplace. Our project is a multi-faceted approach to spread the message of our organization through the development of online professional development modules, events on campus, and training initiatives for students.
Steven Fleming
Ph.D. Candidate
Division of Chemical Biology and Medicinal Chemistry
mRNA Display of Macrocyclic Peptides Targeting the ATP-Binding Site of Kinases
Kinases are important cell regulators orchestrating signals to control cell growth, differentiation, proliferation, angiogenesis, apoptosis, cytoskeletal rearrangement, and metabolism. Kinase malfunctions often engender different types of cancers. Technologies have been developed to rapidly identify new therapeutically relevant kinases, but generating a selective inhibitor thereof is difficult and leads to many kinases remaining uncharacterized. To overcome this barrier, I propose a new kinase-biased mRNA display strategy to quickly develop kinase-specific inhibitors.
Anna Chiarella
Ph.D. Candidate
Center for Integrative Chemical Biology and Drug Discovery
Applying a Novel dCas9 and Bifunctional Molecule System to Control Endogenous Gene Expression in a Disease Setting
Epigenetic pathways are commonly disrupted in human diseases including cancer, yet much is still unknown about the mechanisms by which dysregulation of chromatin regulatory machinery contributes to disease pathology. To investigate and control these complex pathways in live cells, we developed a novel system that will unveil the underlying mechanisms of chromatin regulation using a gene-specific manipulation strategy. To show proof of principle, we will use our system to target disease-relevant genes in model systems.
Amy Dorszynski
Pharm.D. Student
Virtual Pharmacopedia: Modern Drug Database
Due to rigorous course loads and limited elective availability, it is not possible for PharmD Candidates to participate in all elective courses. Often, students do not learn specialty information to excel in their rotations and beyond. To transform this process, Virtual Pharmacopedia is a database housing student-developed multimedia containing pharmacotherapy information taught exclusively in the elective curriculum. Once established, videos will be used to expand student knowledge for rotation preparation, professional interest, and NAPLEX review.
Steven Kiss
Pharm.D./M.B.A. Student
Developing an Infrastructure to Implement Value-based Contracting Arrangements Between Pharmaceutical Manufacturers and Health Systems
Annual price hikes along with shrinking reimbursements and increasing demand for medications create the need for a solution that addresses rising pharmacy spend. This innovation focuses on designing and implementing a value-based contracting framework that will allow UNC Health Care to engage with pharmaceutical manufacturers to maximize clinical and economic value of expensive therapies.
Caleb Vogt
Ph.D. Candidate
Division of Chemical Biology and Medicinal Chemistry
Chimeric Inhibitors of Cytochrome P450 17A1
Abiraterone is an effective drug for the treatment of advanced prostate cancer, but it is converted in patients to a metabolite that promotes the progression of this disease. To address this problem, we seek to design an analog of abiraterone that replaces its key metabolic liability, while maintaining potency and enhancing selectivity at the primary drug target, cytochrome P450 17A1.
Michael Wolcott
Ph.D. Candidate
Learning Sciences and Psychological Studies, School of Education
Escape the Norm: Escape Rooms for Learner Engagement and Collaboration
Escape rooms are an entertainment phenomenon sweeping the nation – but their use in education has been largely overlooked. Our project is leading the field through the design of a pharmacy-themed escape room intended to engage learnings in a fast-paced learning environment that challenges their clinical skills and collaboration abilities. Students will get to put their knowledge to the test and see if they can work together to solve the patient case and escape!
Osteoporosis is a chronic disease associated with high morbidity and mortality rates and affects more than 200 million people worldwide. Surgery is very invasive and the current standard treatment for osteoporotic fractures to promote bone healing. Novel patient friendly/specific and effective biodegradable materials are in high demand. Our goal is to develop a first of a kind combinatory implant for direct injection into the bone or as a 3D bioprinted material for treatment of osteoporosis. Display technologies such as DNA-encoded libraries and mRNA display are transforming drug discovery by miniaturizing the assay of vast libraries of non-canonical molecules. However, these technologies are severely limited by the chemistries available to make the compound libraries. We will use versatile, designer biocatalysts based on natural product biosynthetic enzymes to prepare and test new and novel display libraries. The high incidence of bone pathologies in the craniofacial region due to structural defects (e.g., cleft palate), trauma and disease (e.g., periodontal and cancer) is of special therapeutic interest considering the maxillary/mandibular bone is especially challenging to regenerate. In this project, we propose a new bone regeneration hydrogel that co-releases hesperidin and nitric oxide—two positive modulators of osteogenesis. Community pharmacists are well-positioned to assume a greater role in delivering health services in rural communities. We will create the first multi-state rural community pharmacy practice-based research network called the Rural Research Alliance of Community Pharmacies (RURAL-CP). RURAL-CP’s mission is to reduce rural health disparities by supporting high-quality pharmacy-based implementation research. RURAL-CP will include 100 rural community pharmacies across five southeastern states (Alabama, Arkansas, Mississippi, North Carolina, and South Carolina). The objective of this proposal is to initiate a drug discovery effort using a novel label-free screening technology for finding small molecules that inhibit SETDB1 methyltransferase activity. Our hypothesis is that this effort will lay the foundation toward novel therapeutic agents for liver cancer and may have a broader impact with other cancers including kidney, lung, prostate, and skin. Moreover, validated small molecule inhibitors will also provide key chemical probes to shed new light on the mechanism by which SETDB1 contributes to tumorigenesis and metastasis. Tumor associated fibroblasts (TAFs) play a central role in drug resistance in bladder cancer. Dr. William Kim will study the essential role of TAFs in the resistance of bladder cancer to immunotherapy. Dr. Alexander Kabanov will use polymer micelles to deliver immunostimulatory drugs to enhance the immunotherapy for bladder cancer. Dr. Leaf Huang will use traditional Chinese medicines to induce immunogenic cell death of the bladder cancer cells to enhance immunotherapy for bladder cancer. Chemo-therapies targeting thymidylate synthase (TS) are used to treat human malignancies. However, patients often develop resistance to these drugs through mechanisms related to downstream effects of active site binding. TS is part of a multi-enzyme assembly, termed replitase, which forms in the nucleus during S-phase of cell division. Disrupting complex assembly may provide a new avenue for chemotherapy development. We propose to identify druggable protein-protein interfaces in replitase and target them with virtual screening and subsequent experimental validation. RAS genes encode small GTPases that play critical roles in regulating cell growth, differentiation, and apoptosis. RAS is mutated in approximately 30% of human tumors and is therefore a high-value target across numerous cancer types. Once considered an “undruggable” target, recent efforts suggest that small molecule intervention may be possible. Using a multidisciplinary approach involving structural biology, biochemistry, and medicinal chemistry, we aim to identify highly potent and selective inhibitors of KRAS. In this proposal we aim to overcome the major drawbacks to gene therapy to tumors by developing a systemic gene delivery technology that can actively target circulating monocytes that carry disease-induced inflammation markers. The mRNA or DNA will be incorporated into inert polyplexes and decorated with ligands expressed on blood-born inflamed monocytes. We posit that the systemically manipulated monocytes will extravasate into tumors, differentiate into tumor-associated macrophages and horizontally transfer the gene of interest to the acceptor cells (such as cancer cells, fibroblasts and immune cells) resulting in the gene expressed in the tumor tissue. Through an exciting new partnership between the J. Craig Venter Institute and the Hingtgen Laboratory at UNC, the goal of this project is to leverage the latest advancements in synthetic biology with novel technology in tumor-homing cell therapies to create a ground-breaking new class of cell therapy for cancer. Durable humoral immunity comprised of antibody that can neutralize diverse strains of HIV remains a longstanding challenge in the HIV field. In this project, we seek to develop a cellular therapy that can sustained broadly neutralizing monoclonal antibodies against HIV in vivo. If successful, our work will have broad implications for developing immunity against a diverse array of emerging pathogens. It has been demonstrated that native/commensal microbes in the human body play specific roles in preventing pathogen infections, maintaining metabolic functions, and developing the immune system. As such, microbiome modulation is increasingly being investigated as an approach to prevent or treat diseases. In collaboration with Professor Scott Magness, our proposal will evolve therapeutic microbes in a controlled manner for improved adhesion and colonization in the intestines, which we expect to improve their in vivo performance. Our proposal is to create the first hands-on aseptic technique training simulator device—allowing for an individual to prepare any routine product. Our simulator will document all movements and compare them against established best practice. The individual will receive a report on their performance, including any breaches of technique and overall efficiency of production. This can be used to document an employee’s competency as well as to train new users on proper aseptic technique. Current chronic wound therapies do not adequately address both infection and pathological inflammation. Local delivery of nitric oxide (NO) represents an alternative therapy for treating wounds because of its ability to mitigate infection and inflammation. In this project, our goal is to develop NO-releasing hyaluronic acid (HA) biopolymers that combine the benefits of NO release with HA’s ability to stimulate collagen production in a dual-action wound healing therapeutic. The gut microbiota directly influences human health including the toxicity of many drugs. Preventing this toxicity is a clear unmet medical need. Our idea is to block drug-induced intestinal damage through the molecular control of the gut microbiome. We will accomplish this by pinpointing the gut microbial enzymes responsible for this toxicity and discovering potent, selective and non-lethal inhibitors of these enzymes using high-throughput screening. Our long-term goal is to advance a new therapeutic paradigm – pharmaceutical control of the microbiome to improve human health.
The goal of this 15-month project is to optimize medications for patients with chronic diseases through scaling of Comprehensive Medication Management (CMM) in specialty clinics. This solution is innovative in its focus on transforming specialty pharmacy and its contribution to implementation science. It aims to adapt, implement, and evaluate CMM in six specialty clinics. This project is a collaboration between the Center for Medication Optimization and the UNC Medical Center Pharmacy Department. Preceptors have competing clinical, administrative, and teaching responsibilities and are in need of quick, accessible, and practical precepting resources. Our team aims to develop a tool to be used by clinical preceptors in various health profession disciplines to quickly access preceptor development resources, optimizing teaching approaches and real-time resource accessibility for managing challenges encountered during clinical teaching. The UNC Center for Medication Optimization and the University of Minnesota College of Pharmacy will partner with HealthPartners health plan to implement and evaluate a novel payment strategy designed to drive engagement of practitioners enrolled in a comprehensive medication management (CMM) service delivery network and deliver value to both the payer and network participants. The payment strategy is unique as it marries a traditional fee-for-service payment opportunity that provides a predictable revenue stream for network participants with a two-tiered “pay-for-performance” opportunity that rewards measured impact on quality and achieving defined levels of patient engagement. We will utilize a powerful learning and action collaborative model to accelerate testing and adoption of implementation strategies that allow network members to produce measured improvement in beneficiary health and optimize financial return within the blended payment model. A robust evaluation plan will address impact on network participant engagement and perceived value of the payment structure, impact on beneficiary health and engagement, perception of value of the payment strategy from the perspective of the health plan, and identification of critical actions by MTM-providing organizations to design or adapt service delivery methods that optimize revenue for patient care within the payment model. Anti-PEG antibodies are prevalent, and select PEGylated drugs can induce high antibody titers that compromises their safety and efficacy. Building off of promising proof-of-concept study in rodents, this project involves preclinical validation and dose optimization in pigs that infusion of free PEG can restore the prolonged circulation of PEGylated therapeutics in the presence of substantial anti-PEG antibody titers. In the U.S., prostate cancer is the most commonly diagnosed malignancy, and is the second leading cause of cancer-related death among men. Here, we will evaluate a novel platform technology developed at UNC, and seek to repress key oncogenic targets in incurable metastatic human prostate cancer. We will leverage bi-functional Chemical Epigenetic Modifiers (CEMs), which are small molecules delivered specifically to any gene locus, to control the expression of genes driving prostate cancer. The purpose of this 2-year project is to create, implement, and evaluate a telepharmacy CMM model for complex patients with diabetes in rural primary care clinics. This project could transform pharmaceutical care delivery while evolving the role of the clinical pharmacist. It is a collaboration between the Center for Medication Optimization and the University of Arkansas.
Because of their multi-drug resistant infections, patients with cystic fibrosis (CF) are at an increased risk of development of ototoxicity related to drug exposure, particularly aminoglycosides. This study aims to develop a protocol for pharmacist-driven audiology screening protocol to increase screening rates and early identification of high frequency hearing loss in pediatric patients with CF. Jon Easter The U.S. spends more than $500 billion a year, on the misuse, overuse, and underuse of medications. Our solution combines predictive analytics with individualized clinical pharmacy services to create validated protocols that identifies ‘at risk’ patients and connects them to the right interventions. We believe this synergistic approach will optimize medications for complex patients, resulting in better health outcomes and lower healthcare costs. Collaboration partners include AlignCare LLC and the UNC HealthCare CAMP clinic. To prevent adverse drug events (ADEs) demands our understanding which patient may at high risk. Powerful machine learning is promising for predicting individual risk of ADEs. In this study, we will advance machine learning for predicting individual risk of ADEs. Specifically we will develop a simulated virtual patient cohort with various distributions of ADEs and use the cohort along with cutting edge methods to develop and validate machine learning models to predict individual ADEs.
Division of Pharmacoengineering and Molecular Pharmaceutics
Innovative Combinatory Biomaterials for Bone Repair in Osteoporosis and 3D Bioprinting
Division of Chemical Biology and Medicinal Chemistry
Designer Biocatalysts for Nucleic Acid-Encoded Peptide Libraries
Division of Pharmacoengineering and Molecular Pharmaceutics
Osteogenesis Modulation via Co-Delivery of Nitric Oxide and Hesperidin
Division of Pharmaceutical Outcomes and Policy
Creating the First Multi-State Rural Community Pharmacy Research Network: RURAL-CP
Center for Integrative Chemical Biology and Drug Discovery
Development of SETDB1 Inhibitors for Treatment of Hepatocellular Carcinoma
Division of Pharmacoengineering and Molecular Pharmaceutics
Targeting Tumor Associated Fibroblasts to Enhance Therapy
Division of Chemical Biology and Medicinal Chemistry
Drugging Protein-Protein Interfaces of a Supramolecular Assembly as a Means to Overcome Resistance to Active Site Thymidylate Synthase Inhibitors
Center for Integrative Chemical Biology and Drug Discovery
Small Molecule Inhibitors of RAS Proteins
Center for Nanotechnology in Drug Delivery
Targeting of Inflamed Monocytes for Gene Therapy of Cancer
Division of Pharmacoengineering and Molecular Pharmaceutics
Harnessing Synthetic Biology to Develop Next-Generation Cell Therapies
Division of Pharmacoengineering and Molecular Pharmaceutics
Engineered Cells for Long-Lasting and Potent Vaccination against HIV
Division of Pharmacoengineering and Molecular Pharmaceutics
Evolving Therapeutic Microbes to Improve Colonization and Treatment of Microbiome Disorders
Division of Practice Advancement and Clinical Education
Creation of a Hands-on Aseptic Technique Simulator
Division of Pharmacoengineering and Molecular Pharmaceutics
Nitric Oxide-Releasing Hyaluronic Acid for Wound Healing Stimulation
Center for Integrative Chemical Biology and Drug Discovery
Molecular Control of the Gut Microbiome
Division of Practice Advancement and Clinical Education
Optimizing Medications for Complex Patients: Scaling CMM to Specialty Clinics
Division of Practice Advancement and Clinical Education
Experiential Teaching Assistant: A Preceptor’s Rapid Resource for Clinical Teaching
Division of Practice Advancement and Clinical Education
Driving Quality and Engagement Across a Comprehensive Medication Management Provider Network via a Novel Pay-for-Performance Strategy
Division of Pharmacoengineering and Molecular Pharmaceutics
Dose Ranging Study for the Use of High MW Free PEG to Reduce PEG-associated Pseudoallergic Response
Division of Pharmacotherapy and Experimental Therapeutics
Chemically Catalyzed Epigenetic Gene Regulation in Prostate Cancer
Division of Practice Advancement and Clinical Education
Evaluating a CMM Telepharmacy Model: A New Frontier for Providers and Patients in Rural Communities
Division of Pharmaceutical Outcomes and Policy
Improving Rates of Audiology Screening for Pediatric Cystic Fibrosis Patients Exposed to High-Dose Aminoglycosides through Pharmacist Administered Testing
Division of Practice Advancement and Clinical Education
Connecting Predictive Analytics with Clinical Services to Produce Value-Based care (PA+CS=VBC)
Division of Pharmaceutical Outcomes and Policy
Advancing Machine-Learning for Predicting Individual Risk of Adverse Drug Event
Kevin Frankowski
Center for Integrative Chemical Biology and Drug Discovery
Metarrestin Derivatives as Selective Anti-Cancer Agents with Reduced CNS Exposure
Co-PI: Sui Huang, Associate Professor of Cell and Developmental Biology, Northwestern University
Metastatic cancer remains an urgent, unmet medical need and, while numerous treatment options are available for many cancer patients, those with metastatic diseases have limited options. We developed metarrestin, a first-in-class anti-metastasis drug that recently began phase I human clinical trials at NCI. In this work, we will develop next generation derivatives that more effectively target metastasis including a subset designed with restricted CNS penetration to reduce neurological side effects possible at high doses.
Nate Hathaway
Division of Chemical Biology and Medicinal Chemistry
Novel Bioorthogonal Chemical Epigenetic Modifier Development
Co-PI: Lindsey James, Assistant Professor, Division of Chemical Biology and Medicinal Chemistry
This project will generate and test novel bifunctional chemicals that will be used in combination with CRISPR targeting systems to relocate epigenetic regulators to genes resulting in enhanced transcriptional expression. We will apply this new technology to examine the therapeutic potential in rare human diseases driven by single gene dysregulation events such as the neuromuscular disease Friedreich’s Ataxia.
Shawn Hingtgen
Division of Pharmacoengineering and Molecular Pharmaceutics
Ubercell Technology: Programmable Peptide-Cell Therapy Vehicles
Co- PI: Ronit Freeman, Associate Professor, UNC Department of Applied Physical Sciences
Glioblastoma (GBM) is a devastating brain cancer that often relapses because therapy-resistant cancer cells infiltrate the body at the tumor’s margin. A new partnership between Shawn Higntgen and Ronit Freeman will combine tumor-homing cells and peptide scaffolds into a game-changing approach that seeks out GBM cells and deliver combinations of anti-cancer therapies from small molecules to CAR-T cells. This will create a cell therapy like no other with enhanced tumor recognition while avoiding off-target effects.
Lindsey James
Division of Chemical Biology and Medicinal Chemistry
Development of Novel Therapeutics for Multiple Myeloma
This project aims to develop potent ligands for a novel target recently identified as a crucial mediator of tumorigenicity and novel therapeutic target in multiple myeloma (MM). Newly developed ligands will be used to evaluate the effects of target inhibition on tumorigenicity in MM model systems and explored as potential therapeutics for the treatment of MM.
Rihe Liu
Division of Chemical Biology and Medicinal Chemistry
A Pro-STING Agonist that is Activated in the Tumor Microenvironment
This project aims to develop a pro-gene that is self-cleaved and silenced in normal cells but enzymatically processed and expressed in the tumor microenvironment, resulting in a therapeutic protein product that can activate the innate immune responses such as STING signaling for the combination treatment of hepatocellular carcinoma without affecting normal tissues. The technology platform developed in this project could be widely used in other gene therapy approaches.
Juliane Nguyen
Division of Pharmacoengineering and Molecular Pharmaceutics
Highly Loaded Exosomes as Cell-free Therapeutics for Tissue Regeneration and Repair
Co-PI: Li Qian, Associate Professor, Department of Pathology and Laboratory Medicine
Myocardial infarction and ischemic heart diseases remain the leading cause of death worldwide. While current treatment approaches have significantly decreased mortality from myocardial infarction, those who survive the acute event continue to be at high risk of arrhythmias, strokes, and congestive heart failure. Infarction kills millions of cardiomyocytes, and residual cardiomyocytes have only limited ability to proliferate. Thus, there is an urgent need for new and effective approaches capable of regenerating the infarcted myocardium. The overall goal of this project is to develop a cell-free therapeutic capable of repairing and regenerating injured tissues. We will apply cutting-edge engineering strategies to synthesize safe and highly effective exosomes that can be used as cell-free therapeutics for cardiac tissue regeneration and other chronic wounds.
Sam Lai
Division of Pharmacoengineering and Molecular Pharmaceutics
Development of novel “muco-trapping” mAb constructs for COVID19
The award will fund the development of a number of nebulized monoclonal antibody (mAb)-based therapy against COVID-19. This is based on the “muco-trapping” mAb platform that the Lai Lab has pioneered over the past 10 years. These mAbs, when delivered by inhalation, will neutralize the virus and quickly eliminate them from lung airways.
Bryce Hart
Ph.D. Candidate
Division of Chemical Biology and Medicinal Chemistry
Development of a Small Molecule Ligand for DCAF1
Project Summary: Proteolysis targeting chimeras (PROTACs) are molecules that bind to an E3 ligase and a protein of interest, enabling its degradation. One limitation in the field is the relatively small number of of E3 ligase recruiting ligands. This research aims to develop a first-in-class small molecule ligand for the E3 ligase DCAF1, to facilitate the development of novel PROTACs for numerous disease applications.
Jasmine King
Ph.D. Candidate
Division of Pharmacoengineering and Molecular Pharmaceutics
In-situ Thermogelling Injectable Hydrogel to Enhance Cytotoxic Neural Stem Cell Delivery for Post-Surgical Glioblastoma Multiforme
Project Summary: Cytotoxic tumor-homing neural stem cells (NSCs) are an attractive delivery approach for the treatment of post-surgical Gioblastoma Multiforme (GBM). However, rapid clearance and poor retention of stem cells remain a major challenge that limits their clinical utility. We are developing a biodegradable, in situ forming, thermoresponsive hydrogel scaffold for tumor homing NSCs. Our technology provides an innovative and robust approach to treating GBM.
Sabrina Iskandar
Ph.D. Candidate
Division of Chemical Biology and Medicinal Chemistry
Exploiting Promiscuous tRNA Synthetases to Identify Non-Canonical Peptide Inhibitors of KRAS via mRNA Display
Project Summary: mRNA display is a powerful high-throughput peptide screening method but is limited in its chemical scope, reducing its applicability toward elusive drug targets. Existing technologies that increase the chemical diversity of its libraries have several drawbacks. I propose that orthogonal tRNA synthetases can both compensate for and improve on these technologies, expanding the breadth of proteins that can be selected against using mRNA display. As a proof of concept, I will use a promiscuous orthogonal tRNA synthetase in mRNA display to identify new non-canonical peptide inhibitors of the proto-oncogene KRAS.
Discovery
Albert Bowers
Vice-Chair, Division of Chemical Biology and Medicinal Chemistry
Bryan Roth
Michael Hooker Distinguished Professor, UNC School of Medicine – Department of Pharmacology
Innovative Technology for Selecting Nucleic-Acid Encoded Libraries (NELs) Against Membrane Proteins.
GPCRs represent some of the most therapeutically important targets in modern medicine. Yet GPCRs and other membrane-bound receptors present significant challenges to screening with new display-based methods, such as DNA-encoded libraries and mRNA display. We will develop new technology that allows the direct screening of such nucleic acids-encoded libraries against cell surface displayed receptors and the selective enrichment of receptor binders over background of the complex cellular surface.
Rihe Liu
Associate Professor, Division of Chemical Biology and Medicinal Chemistry
Alex Abuin
Eshelman Institute for Innovation
Engineering a Pro-LEAP2 Therapeutic for the Treatment of Obesity
Obesity and its many associated comorbidities represent a pressing health concern in much of the world. Despite this challenge, the availability of safe and effective anti-obesity therapeutics remains limited. Ghrelin is a key “survival hormone” that activates the GHSR1 receptor in the brain to induce appetite, increase food intake and control energy homeostasis. LEAP2 has been recently discovered to act as an endogenous antagonist of GHSR1, blocking the actions of Ghrelin. However, due to its antagonistic mechanism and pharmacokinetic properties, endogenous LEAP2 may not be suitable as a therapeutic. The goal of our project is to develop a pro-LEAP2 therapeutic through protein engineering and directed molecular evolution, with the goal of increasing its relative levels and/or activity. A LEAP2 analog able to decrease Ghrelin-mediated signaling represents an attractive novel mechanism for obesity therapeutic intervention.
Brian Pietrosimone
Associate Professor, UNC College of Arts and Sciences – Department of Exercise and Sports Science
Jason Franz
Associate Professor, UNC Biomedical Engineering
Development of a Portable Gait Biofeedback System for Rehabilitation of Musculoskeletal Conditions
Abnormal walking gait biomechanics are associated with the development and progression of many chronic lower extremity musculoskeletal conditions, including osteoarthritis. Our project seeks to address this clinical concern by developing technology to restore normal gait biomechanics following lower extremity joint injury for the purpose of maintaining long-term joint health.
Xiaodong Wang
Professor, Center for Integrative Chemical Biology and Drug Discovery
Douglas Graham
Professor, Emory University
Novel TYRO3 Degraders for Treatment of Cancer
The TAM (TYRO3, AXL, MERTK) family of receptor tyrosine kinases play important roles in tumor survival by ectopic expression and/or immune suppression in the tumor microenvironment. Inhibitors of TAM kinases are expected to mediate direct tumor killing and promote anti-tumor immunity. TAM kinases also have kinase-independent functions. Here, we propose to develop novel TYRO3 degraders to disrupt non-canonical functions of TYRO3 and validate their biochemical and functional activities in TYRO3-dependent immune-competent murine cancer models.
Qisheng Zhang
Associate Professor, Chemical Biology and Medicinal Chemistry
Yulan Xiong
Assistant Professor, University of Connecticut
Targeting LRRK2 for Novel therapeutics for Parkinson’s Disease
More than seven million people suffer from Parkinson’s disease, yet existing therapies do not slow or reverse disease progression. Mutations in the LRRK2 gene are the most common genetic causes of Parkinson’s disease, making it a highly promising target to not only alleviate symptoms but also modify disease progression. This project seeks to develop a collection of small molecules that rescue LRRK2-induced neurotoxicity and a novel approach to potentially treat Parkinson’s disease.
Translational
Stephen Eckel
Associate Dean for Global Engagement, Division of Practice Advancement and Clinical Education
Rob Hubal
Associate Professor, Division of Practice Advancement and Clinical Education
Automated Capture and Assessment of Aseptic Technique
We aim to improve aseptic technique competency and detection of compounding errors by carefully observing individuals during preparation of a sterile preparation and then mapping these individual actions to established movement tolerances. This will allow for reports to be generated that demonstrate an individual’s competency and to detect in real-time any breaches of aseptic technique that could lead to concerns about the sterility of the compounded product.
Ronit Freeman
Associate Professor, UNC Department of Applied Physical Sciences
Jim Hagood
Clinical Professor of Pediatric Pulmonary, UNC School of Medicine
Candidate Optimization for Thy-1 Mimetic Antifibrotic Therapy
Progressive lung fibrosis is fatal and incurable. It may result from lung injury, inflammation, infection (including COVID-19), or may have genetic and/or environmental origins, as in idiopathic pulmonary fibrosis (IPF), its most prevalent and pernicious form. Current treatments slow the progression of fibrosis, but do not restore damaged lung tissue. We have developed a new peptide-based approach to reverse lung fibrosis and will identify and validate a chemical lead to test for clinical use.
Jacqui McLaughlin
Associate Professor, Practice Advancement and Clinical Education
CIPhER Teaching and Learning Certificate
The CIPhER Teaching & Learning Certificate (TLC) program is designed to prepare early career pharmacists and educators in identifying, adapting and applying effective evidence-based teaching strategies and skills in a variety of settings including didactic, experiential and patient or community health education
David Lawrence
Chair, Division of Chemical Biology and Medicinal Chemistry
Photothrombolytics: Illuminating a Safe and Efficacious Thrombolytic Therapy
Stroke is the leading cause of disability in the United States and its’ financial impact exceeds $100 billion/year. The formation of a thrombolytic clot is responsible for 85% of all stroke episodes. Unfortunately, the drug used to dissolve the clot has serious side effects and only a 50% success rate. We have developed a technology that uses light to activate the drug at the clot site, potentially eliminating side effects and increasing therapeutic efficacy.
Lida Ghazanfari
Postdoc, Center for Nanotechnology in Drug Delivery
Collaborator: Chinomunso Ahanotu
Medical Student, Meharry Medical College
Use of CAR-macrophage for cell-mediated gene delivery for TNBCs
The potential for gene therapies to treat cancer is constrained by the lack of efficient methods to deliver genes to the tumors. Also, the solid tumor microenvironment remains difficult to treat immunologically. This problem is compounded in triple negative breast cancers (TNBCs) which are somewhat neglected because of their lack of reliable targets. To address these deficits, we will use the CAR-macrophage to as a vehicle for anti-cancer gene therapy.
Joshua Hochuli
Ph.D. Candidate, Division of Chemical Biology and Medicinal Chemistry, Bioinformatics and Computational Biology
Accelerated Docking with Deep Neural Networks and Active Learning
Molecular docking is an established standard for virtual screening of small molecules to nominate drug leads but comes at an extreme computational cost. Docking scores can be accurately reproduced by deep learning models, which can accelerate screening of massive compound libraries by orders of magnitude. This project aims to build docking models for a wide array of proteins, and establish the utility of active learning strategies to improve model performance
Devan Shell
Ph.D. Candidate, Division of Chemical Biology and Medicinal Chemistry
Using Machine Learning to Guide Novel DNA-Encoded Library Hit Discovery and Next Generation Library Production
Small molecule hit discovery via high-throughput screening (HTS) can be a tedious and expensive process. The DNA-Encoded Library (DEL) technology has made breakthroughs by increasing cost/time efficiency of HTS. However, comprehensive data analysis of DEL screens remains a technological hindrance. This research aims to apply machine learning to DEL technology for more efficient data analysis and successful novel hit compound discovery. Hit compounds and machine learning will also be applied for designing next generation DELs.
Jarod Waybright
Post Doc, Center for Integrative Chemical Biology and Drug Discovery
Development of Novel Small Molecule Antagonists of Methyl Lysine Reader Proteins
Methyl lysine reader proteins have an emerging role in multiple malignancies. We are developing novel small molecule antagonists of methyl lysine readers to better understand their role in a variety of cancers. We are focused on improving the pharmacokinetic properties of our ligands to assess the therapeutic potential of methyl lysine reader antagonism in vivo, with the goal of achieving a preclinical lead ligand.
Discovery
Michael Jarstfer, PhD
Assistant Dean for Graduate Education, UNC Eshelman School of Pharmacy
Associate Professor, Division of Chemical Biology and Medicinal Chemistry
Rihe Liu, PhD
Professor, Division of Chemical Biology and Medicinal Chemistry. UNC Eshelman School of Pharmacy
Genetically Encoded Proteolysis Targeting Chimeras
State of the art Proteolysis Targeting Chimeras (PROTACs) are small molecules that induce target degradation by linking a target-binding ligand to a separate E3 ligase ligand. Small molecule PROTAC discovery and development is laborious and constrained by need for target and E3 ligase ligands. We propose overcoming these shortcomings through a platform called Genetically Encoded PROTAC (GE-PROTAC). GE-PROTAC is based on bispecific ligands that can be quickly generated using directed molecular evolution techniques.
Silvia Kreda, PhD
Associate Professor of Medicine, Cystic Fibrosis Center/ Marsico Lung Institute
Adjunct Associate Professor, Department of Biochemistry and Biophysics
Lawrence Ostrowski, PhD
Professor, Department of Pediatrics, UNC School of Medicine, Cystic Fibrosis Center/ Marsico Lung Institute
Therapeutic Oligonucleotides to Correct Splicing Defects Causing Primary Ciliary Dyskinesia
Primary ciliary dyskinesia (PCD) is an orphan, rare disorder due to mutations in >50 ciliary genes causing life-shortening lung disease. Oligonucleotides are ideal therapeutics to correct rare genetic disorders due to their specificity, safety, and economical clinical development and manufacturing. This project proposes to validate a therapeutic oligonucleotide prototype to correct a PCD-causing splicing mutation, and to establish a novel precision/personalized medicine approach for PCD therapeutics.
Rihe Liu, PhD
Professor, Division of Chemical Biology and Medicinal Chemistry. UNC Eshelman School of Pharmacy
An Innovative Immunotherapeutic Target and Its Inhibitor for Treating Triple Negative Breast Cancer (TNBC)
Strong evidence indicates that the key to improve cancer immunotherapy is the development of combination treatment that can synergistically enhance the therapeutic efficacy of existing immune checkpoint inhibitors or innate immune activators. This project aims at developing a therapeutic agent to block the biological activities of a novel signaling molecule that plays a pivotal role in suppressing the maturation and differentiation of dendritic cells and T cells. The success of this project would validate a novel drug target and generate the corresponding therapeutic molecule for the combination immunotherapy of TNBC and potentially other solid tumors.
This project is co-funded with the UNC Lineberger Comprehensive Cancer Center
Grégory Scherrer, PharmD, PhD D
Associate Professor, Department of Cell Biology and Physiology, UNC Neuroscience Center, Department of Pharmacology
Jeffrey Aubé, PhD
Eshelman Distinguished Professor of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy
Developing Converging Non-Addictive Analgesics Against Pain Unpleasantness to End the Dual Epidemic of Chronic Pain and Opioid Addiction
Opioids analgesics are widely used to treat pain. However, they can generate harmful side effects such as addiction, and have only limited utility against certain types of chronic pain. To treat pain more effectively and safely, we identified the brain neurons at which peripheral pain signals converge to produce the unpleasant quality of pain, and are developing novel non-opioid compounds that can silence these neurons to eliminate the unpleasantness of any painful injury or disease.
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Kevin Frankowski, PhD
UNC Eshelman School of Pharmacy, Center for Integrative Chemical Biology and Drug Discovery
Sigma Receptor Modulation as an Opioid-Free Approach to Pain Therapy
Prescription opioid drugs remain the prevailing treatment for chronic pain, contributing to opioid dependence and the opioid-related health crisis, underscoring the urgent need for new approaches in pain management. This project will develop our novel sigma receptor ligand classes for pain management as an alternative to opioid drugs, which carry high risks of abuse and overdose potential.
Andrea Nackley, PhD
Duke University, Anesthesiology
Peripherally-Targeted Adrb3 Antagonists for the Treatment of Pain
Chronic pain constitutes one of our nation’s largest healthcare problems, yet is ineffectively treated by conventional pharmacotherapies (eg, opioids) that adversely effect the central nervous system. Our objective is to develop a drug discovery platform for the novel peripheral target Adrb3 that includes 1) chemical synthesis of new potent, peripherally-selective Adrb3 antagonists and 2) preclinical testing of their analgesic efficacy and side-effects. If successful, this work will advance promising new analgesics into clinical trials.
Grégory Scherrer, PharmD, PhD
UNC School of Mesicine, Department of Cell Biology and Physiology,
UNC Neuroscience Center, Department of Pharmacology
Resolving the Neurobiological Mechanisms of Opioid-Induced Reward, Dependence, and Respiratory Depression to Identify Novel Therapeutics Against Opioid Addiction and Overdose Death
Opioids are effective analgesics, however, these drugs also produce harmful side effects that have generated an epidemic of opioid addiction and overdose deaths. This project aims to elucidate and inhibit the neurobiological mechanisms of opioid-induced reward and dependence, which cause addiction, and of opioid-induced respiratory depression, which is the main cause of overdose death. To this aim, this research will first utilize RNA sequencing technologies to identify opioid-sensitive neurons in the brain. The genes expressed by these neurons will then be characterized to discover drug targets for the development of innovative treatments that can prevent and treat opioid use disorders to battle the opioid epidemic.
Paul Armistead, MD, PhD
UNC School of Medicine, UNC Lineberger Comprehensive Cancer Center
Nilu Goonetilleke, PhD
UNC School of Medicine, Microbiology and Immunology
T Cell Immunotherapies Targeting HLA-E Antigens for the Clearance of EBV- and HTLV-Associated Malignancies
Many lymphomas result from virally induced malignant transformation of normal lymphocytes. Engineering immune cells to target virally derived peptides, which are presented on the cell surface by HLA molecules, could enable new immunotherapeutics. The genetic sequence of HLA-E is conserved across the human population so any discovered peptide/HLA-E complexes could lead to broadly applicable immunotherapeutics. This project aims to discover viral peptides complexed to HLA-E molecules as well as T cell receptors that recognize them.
Kevin Frankowski, PhD
UNC Eshelman School of Pharmacy, Center for Integrative Chemical Biology and Drug Discovery
Rosyln Bill, PhD
Aston University, College of Health & Life Sciences
Inhibiting Aquaporin-4: A New Approach for the Treatment of Stroke and CNS Injuries
Our goal is to develop preclinical inhibitors of aquaporin channel function, a promising approach for preventing the damage resulting from the CNS edema affecting millions of patients every year. This early-stage collaboration will optimize small molecule hit scaffolds and validate their suitability (efficacy, selectivity, safety and pharmacokinetic properties) for preclinical development. This project is an exciting new direction for the treatment of traumatic CNS injuries and stroke with enormous potential benefit to patient health.
Lindsey James, PhD
UNC Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry
Follow on Funding: Development of Novel Therapeutics for Multiple Myeloma
This project aims to further develop potent ligands for a novel target recently identified as a crucial mediator of tumorigenicity and novel therapeutic target in multiple myeloma (MM). Newly developed ligands will be used to evaluate the effects of target inhibition on tumorigenicity in MM model systems and explored as potential therapeutics for the treatment of MM.
Barbara Vilen, PhD
UNC School of Medicine, Department of Microbiology and Immunology
Restoring Lysosome Function Using a Therapeutic Antibody to Prevent Disease Flare in Systemic Lupus Erythematosus
Systemic lupus erythematosus (SLE) is an autoimmune disease where the immune system becomes activated by self-proteins. We recently discovered that lupus-prone mice and patients with SLE have diminished lysosome function. This promotes the accumulation of undegraded waste inside immune cells and on their surface. This project proposes to determine whether a bispecific antibody aimed at restoring lysosome function attenuates the progression of lupus.