2023-2024 Pre-Doctoral Fellow Projects by Research Category

Clinical and Translational Sciences (includes pharmacotherapy, experimental therapeutics, PK/PD, modeling and simulation)

Jessica Barry, University of Minnesota

Mentor: Dr. Angela Birnbaum

Research Title: Physiologically-based simulations to predict lamotrigine exposure and mechanistically quantify pharmacokinetic changes during pregnancy

“Our project aims to predict drug exposure changes in pregnant patients and their fetus. Instead of obtaining multiple blood samples from pregnant patients to quantify drug exposure over time, we build models that rely on knowledge of how the body metabolizes the drug based on factors like age, blood flow rate, liver function, and kidney function. Additionally, we will use animal models to understand how much drug is in different tissues, like brain or fetal tissue. Many of these parameters change during pregnancy as the fetus grows. Through model refinement and comparing model results to real data, we can improve our predictions and make assessments about drug dosing changes to ensure a patient’s drug therapy continuous to work. In the future, we can extend our model to be able to make predictions about fetal drug exposure.”

 

Alyssa Min Jung Kim, Purdue University

Mentor: Dr. Seung-Oe Lim

Research Title: Cold to Hot: Inducing Localized Inflammation in the Tumor Immune Microenvironment

“Immunotherapy is a form of therapy that relies on and utilizes the body’s immune system to combat cancer. However, clinical studies have shown that the success of immunotherapy in patients highly depends on the immunological environment surrounding the tumor. There are higher response rates to immunotherapy in immunologically inflamed, i.e., “hot” tumors, which are typically characterized by greater infiltration of immune cells that are capable of targeting and eradicating tumor cells into the tumor environment, compared to the counterpart “cold” tumors marked by the absence of immune cell infiltration and/or the presence of suppressive regulatory cells that prevent the favorable actions of immune cells. With a significant portion of patients with immunologically “cold” tumors being non-respondent or refractory to immunotherapy, this clinical challenge points to an unmet clinical need for innovative strategies that can convert “cold” tumors into “hot” tumors and, thus, more responsive to therapy. Therefore, the goal of this project is to present a novel therapeutic strategy that can induce such change as well as make immunotherapy more available as a treatment option to a broader patient population. We will design and present an antibody, a form of immunotherapy, that not only modulates the immune system within the tumor, but also delivers a safe immunogen specifically and locally into the tumor so that a sufficient immune response can take place against cancer cells even in those that are immunologically cold. We seek to address the important obstacle of cold unresponsive tumors by establishing the means of “warming” these tumors up, ultimately making them responsive to immunotherapies, as well as studying the different factors that mediate this change. Altogether, this project strives to enhance human health by improving the efficacy and success rates of immunotherapy across many cancer types and, therefore, reducing the morbidity and mortality associated with cancer.”

 

Nam H. K. Nguyen, University of Florida

Mentor: Dr. Jatinder Lamba

Research Title: CRISPR Synthetic Lethality Screen Identifies Genomic Resistant/Sensitive Modulators of Standard Chemotherapy in Pediatric Acute Myeloid Leukemia (pAML)

“Acute myeloid leukemia (AML) has one of the biggest death contributions in all leukemia subtypes in both the pediatric and adult populations. It was estimated that 5 years OS of pediatric is about 70% and adult is only 25%. It is a devastating disease and we need to have better care for our patients. AML is a heterogeneous disease with limited drug treatment options, where cytarabine and daunorubicin also known as 7+3, has been the standard backbone chemotherapy for almost 5 decades despite recently newly approved drugs. These newly approved agents are typically used in combination with 7+3 or in subsequence of this standard chemotherapy once the patient relapse. Because of limited therapy options, chemotherapy resistance is a significant factor that can affect patients’ outcomes. Therefore my research is to understand the genetic modulators associated with response to chemotherapy when treatment are given to AML patients, and to discover novel pathways and targets that can overcome drug resistance. Ultimate goal is to improve patient outcomes My dissertation work broke into two main parts: Firstly, is to use CRISPR technology with a custom library to perform synthetic lethal screen multiple AML cells with common used drug in AML treatment. Herein, our custom library has three components: 1) all AML and leukemia prognostic genes, 2) all PKPD genes of our standard of care treatment and 3)a druggable genome with approved agents. At the CRISPR screen, I will identify a list of drug resistance genes and sensitive genes for chemotherapy then this will be integrate into clinical integration. I hypothesize that drug resistance genes will show better outcome with lower expression and vice versa for drug sensitive genes, where lower expression collated to clinical outcomes. Futher significant genes from CRISPR screen with prognostic potential will be further be investigated mechanistically. At the end of my dissertation work, I hope to identify novel genes and pathway associated that lead to drug resistance. Also, my work will profile a list of genes with the prognostic potential to predict patient outcomes. Hopefully, this will provide insight for drug combination guided by gene expression. Because our custom CRISPR gene contain druggable genome, we hope to use that repurpose approved drug that can be combined with chemotherapy to overcome drug resistance”

 

Madeline Lipp, University of Pittsburgh, Second Year Fellow

Mentor: Dr. Kerry Empey

Research Title: Effect of RSV maternal vaccination on tissue resident memory T cell response

“Respiratory syncytial virus (RSV) is a common virus that is associated with significant morbidity and mortality in children under 5 years of age. It is particularly dangerous for infants, as their immature immunity often leads to severe disease requiring hospitalization. Severe RSV in early life is also associated with development of asthma later in life. It is therefore very important to prevent RSV in infants.

Maternal vaccination, whereby a pregnant woman receives an vaccine in the third trimester in order to deliver high amounts of anti-RSV antibodies to the developing fetus, is considered a safe and effective way to protect infants in early life. There are currently several RSV maternal vaccine candidates in clinical trials. It is important to consider, however, how maternal antibodies may affect the long term response to RSV. Our lab has shown that infection with RSV in the presence of high levels of maternal antibodies can negatively impact the immunological memory response. In particular, a crucial subset of immune cells, called tissue resident memory T cells (TRMs), offer robust and rapid antiviral protection when pathogen reexposure occurs. My preliminary data suggests that TRMs are differentially affected by the presence of maternal antibodies at primary RSV infection. Through my project I hope to improve a maternal vaccine formulation in order to optimize the TRM response to RSV.”

 

Spencer Peh, University of Kentucky

Mentor: Dr. Jill Kolesar

Research Title: Targeting glutaminase inhibition pathways to overcome artesunate chemoresistance in KEAP1 loss of function non-small cell lung cancer

“Our proposed study will establish preclinical efficacy and toxicity of artesunate and telaglenastat (CB-839) combination and identify novel biomarkers of response or resistance to the combination in difficult to treat non-small cell lung cancer. The aims of this project are to 1) Elucidate the mechanism of synergy and identify novel biomarkers of response or resistance to artesunate and glutaminase inhibition. 2) Establish preclinical efficacy of artesunate and telaglenastat combination in KEAP1 loss mice model.”

 

 

Drug Delivery, Bioengineering (includes nanomedicine, devices, biotechnology, protein delivery and characterization, and biopharmaceuticals)

 

Jason Grunberger, University of Utah

Mentor: Dr. Hamid Ghandehari

Research Title: Treatment of Hepatocellular Carcinoma Using Novel Double Shelled Silica Nanoparticles for Controlled Drug Delivery

“Originally, I proposed my research AIMs as a classical nanomaterials project in which the goal was to synthesize, characterize, and assess the nanoparticles’ efficacy for drug delivery. However, over the last year I have transitioned to elucidation of silica nanoparticle toxicity and safety evaluation. This change is a direct result of a change in my interests within this field. All nanomaterials for clinical applications must have comprehensive screening of toxicity for use in FDA approved products as well as preventing adverse reactions in participants during clinical trials. During my research of silica nanoparticles, I saw a critical gap in knowledge of toxicity in these nanomaterials. So, by transitioning my research to toxicological evaluation of silica nanoparticles, I will have a greater impact on future clinical development of these systems, which was my ultimate goal to begin with.”

 

Drug discovery/medicinal chemistry

Kelsey Holdaway, University of Minnesota, Dr. Paul B. Myrdal Memorial Pre-Doctoral Fellowship in Pharmaceutics

Mentor: Dr. Gunda Georg

Research Title: Development of Selective, Allosteric Inhibitors of Cyclin-Dependent Kinase 2 for the Therapeutic Treatment of Cancer

“In diseases such as ovarian, breast, and colorectal cancers a particular enzyme termed CDK2 is overactivated, which leads to cancer cell growth. One approach toward the treatment of these types of cancers is to inhibit CDK2 and thus inhibit cancer cell growth. A main challenge in this approach is how to selectively target CDK2 over other similar enzymes, which if also inhibited will cause negative side effects. One such strategy to overcome this challenge is to design inhibitors that bind to a location on CDK2 that is unique and less conserved amongst other similar enzymes, which would result in improved selectivity and fewer or no undesirable side effects. Our lab has identified two such unique locations on CDK2 that are suitable for selective binding of an allosteric inhibitor. For the first site, our lab has already developed inhibitors capable of binding, however, they exhibit a problem with being outcompeted for binding by a small protein that activates CDK2. In order to improve the ability of our inhibitor to preferentially bind at this site, we propose to develop inhibitors capable of permanently binding. As the other protein binds in such a manner as it attaches and detaches cyclically, a permanently binding inhibitor could overcome the issue of being outcompeted. For the second site, computational analysis will be performed to help identify an inhibitor that would be compatible with binding at this location and inhibit the enzyme selectively. The outcome of this analysis is expected to identify an inhibitor that is compatible with binding to CDK2 at the specific location. With this knowledge, a variety of inhibitors can be synthesized and subsequently tested for their ability to selectively bind at this location and inhibit CDK2. Upon synthesis of inhibitors capable of selectively binding at either of these locations, the goal will be to test for inhibition activity against CDK2 and test the analogs for anticancer activity in several ovarian cancer cell lines. From this, it can be deduced how effective the inhibitors are at inhibiting CDK2 activity and thus inhibiting cancer cell growth. Ultimate goals are to test these inhibitors in animal models of cancer and then in clinical studies.”

 

Garrison Nickel, University of Utah

Mentor: Dr. Katharine Diehl

Research Title: Histone Lactylation: A Metabolite-derived mechanism of gene regulation

“In humans (and all eukaryotes), DNA is packaged by wrapping it around histone proteins. These histones can be ‘marked’ by the cell, through attaching small molecule labels. The histone code hypothesis posits that these marks act as ‘road signs’ for the genome, altering the behavior of proteins that interact with the genome and causing changes in the amounts of each gene that are expressed. Recent research has identified a new histone ‘mark’ that comes from the small molecule lactic acid. I am interested in determining what this mark instructs the genome to do. I am studying this by looking for proteins that change their genome-binding behavior in response to the presence of this mark. Additionally, I’ve found a protein (Sirtuin 6) that is capable of removing this lactyl mark, and am investigating the extent of that activity and the impact it has on the genome.”

 

Howard J Phang, University of California, San Diego

Mentor: Dr. Anthony Molina

Research Title: Using Human Cell Models of Aging to Identify Modulators of Mitochondrial Function

“A growing body of research indicates that your cells’ ability to generate energy via mitochondria plays an important role in healthy aging and preventing age-related illness. The goal of my project is to develop a platform to accelerate the discovery of substances with the ability to make mitochondria work better or more efficiently. This will be done through laboratory techniques that will use human skin cells to test and measure individual chemicals’ ability to affect mitochondrial function.”

 

 

Christopher Stevens, University of Wisconsin-Madison, Second Year Fellow

Mentor: Dr. Weiping Tang

Research Title: A Glycopeptide Conjugate Platform for Targeted Protein Degradation through the Lysosome

“In the toolbox of therapeutic treatment, it is important to be able to bind and degrade specific disease relevant proteins in order to modify cell function or overcome the resistance to inhibition-based therapeutics. While there are several current methods to achieve this, they are limited to targeting proteins that are already inside the cell, which only accounts for a fraction of the total relevant proteins. My goal is to create a platform for targeted protein degradation that can target those extracellular and cell-membrane associated proteins. I plan to utilize the mannose-6-phosphate receptor and its native function in the internalization and degradation of proteins through the lysosome. My goal is to create a series of glycopeptide conjugates that can bind the proteins of interest and then direct them towards the lysosome for degradation. Once we can effectively achieve targeted degradation through the lysosome, my goal is to modify the conjugate for targeting towards a variety of relevant targets in cancer immunotherapy and cardiovascular disease states. This will expand the current options for disease treatment and help overcome many issues in drug resistance.”

 

Ian Steinke, Auburn University

Mentor: Dr. Rajesh Amin

Research Title: Design, and development of novel selective LXR/PPAR dual agonists for Alzheimer’s disease

“Lipids are essential components of the structure and function of the brain. Significant changes involving lipid regulation are observed in patients with Alzheimer’s Disease (AD). Our project will investigate the role of metabolic stimulating compounds to improve changes in lipid metabolism associated with AD pathology. Understanding the mechanisms involving AD associated changes in lipid will provide novel approaches for therapeutic intervention in this currently incurable disease.”

 

Nicholas Young, University of California, San Francisco, Second Year Fellow

Mentor: Dr. Charles Craik

Research Title: In silico and biochemical screening of TMPRSS2 inhibitors as an antiviral strategy against SARS-CoV-2

“In the last two years, several vaccines and a therapeutic have been developed and distributed to diminish the spread of COVID-19. The vaccines give our bodies short-term immunity and the therapeutic targets the virus to minimize spread within the body. These treatments were successful in minimizing the spread; however, with the recent rise of immune-evading variants (e.g. omicron) and the potential for new coronaviruses to develop, a new antiviral strategy is needed. The goal of my project is to develop a treatment to combat the spread of SARS-CoV-2 within the body, but by targeting a human enzyme instead. For the virus to infect cells, human proteases (enzymes that act as scissors) must cleave spike protein presented on the surface of viral particles. My project asks can we develop a potent small molecule inhibitor that targets TMPRSS2, a human protease implicated SARS-CoV-2 and other coronavirus infection pathways. To develop this therapeutic I am using large-scale docking to computationally screen more than 200 million molecules. The potency of top-scoring molecules can then be measured against TMPRSS2 and viral models. Through these methods, my project can identify new chemical entities that can serve as inhibitors against SARS-CoV-2 and other viruses.”

Pharmaceutical Technology (includes formulation sciences, dosage form design, materials science, physical pharmacy)

 

Angela Ren, University of Texas at Austin

Mentor: Dr. Feng Zhang

Research Title: Repurposing twin-screw extruders: Development and characterization of drug delivery systems for the pulmonary and subcutaneous routes of administration

“The goal of the first part of my research is to develop a new method for manufacturing powders for inhalers that improves product quality and consistency compared to powders produced using traditional methods. Powder inhalers are used to treat respiratory diseases such as asthma. They consist of a custom inhaler which holds a powder mixture of the active and a few inactive ingredients. Particle size of the active, mixing method, and uniformity of the powder mixture determine whether the powder can be successfully delivered to the deep lung to work. Commercial products are prepared using mixers that hold a limited volume of blend and require the first batch to finish before preparing the next batch. There are issues associated with these processes, including inconsistency between batches, and numerous steps. To solve these issues, we invented a method to prepare the powders using a twin-screw extruder, which is a mixer that is open on both ends and driven by two rotating screws. The powder is fed in and moves horizontally through to the exit while being mixed by the screws. Materials are constantly flowing in and out of the mixer, which results in more uniform product. We produced powders using a range of material feed rates and screw rotation speeds to study the impact of amount of mixing on the product quality. We compared the powders prepared using two different screw designs and compared our powder performance to powders prepared using traditional methods. Finally, we analyzed the drug distribution in each blend and conducted experiments simulating the inhalation process in a patient to determine the amount of active delivered to the deep lung. The goal of the second part of my research is to develop and characterize a replicate implant of Nexplanon, which is a birth control implant that is inserted into the upper arm. We want to understand how drug is released from the implant, and how the drug physical form affects the release rate. The implant is about the size of a matchstick, consisting of a core and skin layer. The core consists of solid and dissolved drug in an ethylene copolymer containing 28% vinyl acetate (EVA 28). The skin consists of EVA 15, and only covers the implant length. Since there is no skin layer covering the ends, drug releases through two different mechanisms through skin and ends. The skin serves as a rate controlling layer due to its lower VA% and the excess solid drug in the core enables a near-constant release rate through the skin. Release through ends is determined by the dissolution of solid drug into EVA 28 and the concentration of dissolved drug across the implant core. We will study the contribution of the two drug release processes to the total drug release. We will also investigate the rate of drug crystal dissolution and release when the implant is placed in different solvents. Finally, we will look at how temperature and drug amount affect the formation and location of drug crystals.”

Pharmacology, Toxicology (includes cell biology, chemical biology, and pharmacognosy)

Jack Keady, The University of Kentucky

Mentor: Dr. Jill Turner

Research Title: Investigation into the sex and cell specific impacts of nicotine withdrawal in the murine hippocampus

“Despite the well-known negative consequences of smoking, approximately 12.5% of Americans are smokers, and smoking remains the leading cause of preventable death in the United States. Current FDA approved medications for smoking cessation lack long-term efficacy, which is often attributed to these drugs’ ineffectiveness on mitigating the non-craving nicotine withdrawal (WD) symptoms of cognitive deficits (i.e., difficulty concentrating) and affective dysfunction (i.e., increased anxiety, anger, and depression). Furthermore, these non-reward WD symptoms are often divergent in terms of sex, with women reporting higher anxiety scores when undergoing nicotine WD when compared to men. One critical brain region contributing to both WD domains is the hippocampus, which presents sex-dependent circuitry differences as well. The goal of my project is to evaluate how sex and cell specific transcriptomic changes occurring in the murine hippocampus impact the nicotine WD endophenotypes of cognitive deficits and affective dysfunction. To achieve this goal, we will investigate the impact of nicotine and forced nicotine WD in male and female mice simultaneously undergoing contextual fear extinction and novelty induced hypophagia, which assess hippocampally dependent memory and anxiety-like phenotypes respectively. Pairing these behavioral models with next generation single cell sequencing of hippocampal samples will provide a deeper understanding of how sex interacts with hippocampally mediated nicotine WD endophenotypes. The combination of well established behavioral assays and cutting edge next generation sequencing will generate the necessary data for identification of novel targets for the development of sex specific smoking cessation pharmacotherapies.”

 

 

Emily Prantzalos, University of Kentucky, AFPE Regional Award

Mentor: Dr. Jill Turner

Research Title: Role of Neuregulin 3-ErbB4 Signaling in a Murine Model of Co-Morbid Nicotine Dependence and Schizophrenia

“The World Health Organization estimates that 1.3 billion people worldwide are tobacco users and, without cessation support, only 4% of attempts to quit tobacco succeed. Additionally, rates of substance-use disorders among psychiatric patients are consistently higher than in the general population, with reports of at least a 4-fold difference in smoking rates between controls and patients with schizophrenia. Both nicotine dependence and schizophrenia have been shown to have strong genetic influences, with common variations in the gene Neuregulin-3 (NRG3) and its cognate receptor ErbB4. Therefore, the overarching goal of this fellowship-training proposal is to explore the role of the NRG3-ErbB4 signaling pathway in the relationship between nicotine dependence and co-morbid schizophrenia. To accomplish this, we are evaluating two central aims: 1) Determine ErbB4 cell-specific contributions to nicotine withdrawal behavioral phenotypes and efficacy of the antipsychotic Aripiprazole in ameliorating these effects, and 2) Characterize expression patterns of NRG3-ErbB4 signaling within the prefrontal cortex and identify the molecular alterations induced during chronic nicotine and withdrawal that may be used as novel drug targets for smoking cessation therapies. Our approach utilizes a novel genetic mouse model of both nicotine dependence and schizophrenia in a multidimensional approach to provide insight into the underlying mechanisms that define the NRG3 signaling pathway and its role in nicotine dependence, potentially providing a link between nicotine use and its highly co-morbid psychiatric disorder, schizophrenia.”

 

Social and Administrative Sciences

Sarah Khor, University of Washington, Second Year Fellow

Mentor: Dr. Josh Carlson

Research Title: Incorporating Equity into Healthcare Decision Making

“There is an increasing demand to incorporate health equity into healthcare policies and decisions. The US Department of Health and Human Services’ Healthy People 2030 initiative listed eliminating health disparities and achieving health equity as one of the key goals of the nation’s efforts to improve health and well-being of all people. However, it remains unclear how and to what extent equity should be considered in actual healthcare decision making, especially when faced with system budget limitations.  The overall goal of this proposed project is to develop an understanding on how to incorporate equity into healthcare decision making.  First, we will examine the extent to which our society has been currently trading off health equity for overall health improvement by studying the relationship between new oncologic drug introduction and disparities in health and economic outcomes. Second, we will evaluate the usefulness of tools that are available to reduce health disparities by simulating the health and health disparity implications of adopting “fair” machine learning algorithms to support oncological treatment decisions.  Third, we will conduct discrete choice experiments to derive quantifiable equity weights that reflect the equity preferences of the US public.  Results of this study will provide the motivation, evidence, and inputs that will bring us closer to prioritizing equity in healthcare decisions to eliminate health disparities.”

 

Amna Rizvi-Toner, University of Michigan, ASHP-AFPE Fellowship

Mentor: Dr. Karen Farris

Research Title: Oral Anticancer Agents: Symptom Self-Management and Healthcare Utilization

“The primary goal of my project is to understand the role patient self-efficacy plays in their ability to self-manage symptoms arising from oral anticancer agents (OAA), as well as their use of healthcare services. Additionally, my project seeks to understand the patient experience while taking OAA, which includes their quality of life, OAA adherence, self-efficacy levels over time, symptoms that result from the OAA, symptom severity, and behaviors to self-manage symptoms. Lastly, my project also aims to understand the cancer care clinicians’ perspectives on supporting patients with managing OAA symptoms. Cancer care clinicians will include the following members of the patients’ cancer care team: physicians, pharmacists, advanced practice providers (e.g. nurse practitioners and physician assistants), and nurses.”

 

Huilin Tang, University of Florida

Mentor: Dr. Jingchuan Guo

Research Title: Newer Glucose-Lowering Drugs and Risk of Parkinson’s Disease in People with Type 2 Diabetes

“Parkinson’s disease (PD) is one of the world’s fastest-growing nervous disorders. It affects nearly one million people in the United States. However, there are no effective treatments for PD. Because type 2 diabetes (T2D) and PD are both age-related diseases, they shared similar pathways including insulin signaling. Thus, newer glucose-lowering drugs (GLDs) may be potential treatments for PD. In this study, I will use the Medicare administrative data to evaluate the association between newer GLDs and the risk of PD in people with T2D by estimating the average treatment effects among the overall population and identifying which subgroups could get the most benefits.”

 

 

Rachel Wittenauer, University of Washington, Pre-Doctoral Fellowship in Health Outcome Disparities

Mentor: Dr. Andy Stergachis

Research Title: Equitable access and reimbursement for pharmacy-based services: A case study of adult vaccinations

“Community pharmacies provide important health services: in addition to dispensing medications, they provide vaccinations, screening and testing, medication management counseling, addiction management, diabetes education, and more. However, not everyone has good access to pharmacies depending on where they live. “Pharmacy deserts” are neighborhoods which are both low-income and have low access to pharmacies. These neighborhoods often exist in rural areas and areas with historically marginalized populations, such as majority-Black neighborhoods. This lack of access may further exacerbate health inequities already faced by these communities. While evidence on locations, characteristics, and impacts of pharmacy deserts is growing rapidly particularly in response to the COVID-19 pandemic, there is currently no comprehensive map of where these communities are located at the local level throughout the US. My dissertation research will define this national map and characteristics of populations living in pharmacy deserts, and subsequently evaluate whether pharmacy desert residence has a negative impact on patient health outcomes related to pharmacy-provided services (Aim 1). I will also evaluate whether higher payor reimbursement amounts to pharmacies for pharmacy-based health services improves access to those services. This re-alignment of reimbursement to incentivize valuable services rather than only incentivizing dispensing of medications is often known as “provider status” for pharmacists, and has long been a priority of community pharmacists to enable them to continue to serve their communities. I will accomplish this evaluation by taking advantage of the natural experiment that a select number of states have implemented this “provider status” reimbursement policy for pharmacies while others have not (Aim 2)”