2022-2023 Pre-Doctoral Fellows

2022-2023 Pre-Doctoral Fellow Projects by Research Category

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

Jessica Beers, University of North Carolina at Chapel Hill

Mentor: Dr. Klarissa Jackson

Research Title: An In Vitro Investigation of the Metabolism, Pharmacokinetics, and Hepatotoxicity of Cannabidiol

“The overall goal of this project is to understand the metabolism of cannabidiol (CBD) in the liver, and to explore the potential relationship(s) between the metabolic pathway of CBD and the risk of CBD-related adverse effects in patients and consumers taking this drug. CBD is a popular ingredient in consumer products and an FDA-approved treatment for seizures caused by rare and severe forms of epilepsy in children. This drug has been shown to cause liver toxicity at therapeutic doses in both patients and healthy volunteers. The cause(s) of this toxicity are unknown but may be related to how CBD is cleared from the body by drug-metabolizing enzymes in the liver. Prior work has provided some insight on the drug-metabolizing enzymes involved in CBD metabolism; however, the enzyme contributions related to formation of major CBD metabolites remain unclear. This project aims to identify the drug-metabolizing enzymes involved in generating the major metabolites of CBD, and to test whether changes in the activity or expression level of these enzymes (caused by genetic differences or interacting drugs) will affect the incidence of toxicity in liver cells treated with CBD. Data obtained from these experiments will also be used to help determine the mechanism(s) of CBD-induced livery injury. Newly discovered information on the metabolism and toxicity of CBD will be incorporated into a mathematical model that describes the relationship between CBD exposure and toxicity in diverse patient groups.”

 

Cody Black, University of Texas at Austin

Mentor: Dr. Grace Lee

Research Title: Clinical and Molecular Epidemiology of Non-carbapenemase Producing Carbapenem-Resistant Organisms

“Antimicrobial resistance (AMR) is an urgent and contemporary danger to public health. Organisms that are resistant to the carbapenem class of antibiotics, considered a last-line treatment, are among the top 10 current threats to global health, according to the Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO). Referred to as Carbapenem-Resistant Organisms (CRO), these pathogens are commonly represented by Pseudomonas aeruginosaAcinetobacter baumanii, and members of the Enterobacterales (formerly Enterobacteriaceae) order including Klebsiella pneumoniae and Escherichia coli. CROs tend to harbor numerous mechanisms of resistance, with drug inactivation through carbapenemase enzyme production being the most recognized. Despite this, approximately 50% of carbapenem-resistant Enterobacterales (CRE) and 2% of carbapenem-resistant P. aeruginosa (CRPA) in the U.S. are non-carbapenemase producing. The resistance mechanisms employed by these non-carbapenemase producing CRO (NCP-CRO) remain poorly characterized and thus not as readily identifiable, imposing a major challenge in patient care. A combination of mechanisms have been implicated in leading to carbapenem resistance in NCP-CRO isolates. Namely, production of extended-spectrum cephalosporinase production (e.g., SHV, CTX-M, AmpC) in conjunction with outer membrane porin deficiency (i.e., OmpK36) or loss (i.e., OmpK35) and insertion of IS elements. Research and clinical experience have shown that the degree to which any of these resistance mechanisms are present in a CRO pathogen depends on the species and strain. In addition to better understanding these clinical predispositions, new diagnostics are needed to better detect non-carbapenemase resistance mechanisms present infections associated with CROs. For these reasons, the aims of this study are to 1) identify the role of porin alterations on carbapenem resistance in NCP-CRO strains and the effect of these alterations on the activity of novel β-Lactam/β-Lactamase inhibitors, and 2) construct and validate a predictive model to identify CRE infections and associated clinical outcomes in a region with a high prevalence of NCP-CRE. We propose to accomplish these aims by employing an array of from genomic, proteomic, and phenotypic studies paired with clinical studies of NCP-CRO associated infections across five hospitals in the South Texas region. The proposed research would lay important groundwork towards developing a rapid diagnostic tool for NCP-CRO. Such a tool would provide new strategies for the detection and surveillance of these infections, afford guidance for therapeutic decision making, and help elucidate the mechanisms and implications of carbapenem resistance.”

 

Keito Hoshitsuki ,University of Pittsburgh

Mentor: Dr. Christian Fernandez

Research Title: Prevention of asparaginase immunogenicity by targeting the adenosine signaling pathway

“The overall goal of this project is to improve pediatric acute lymphoblastic leukemia (ALL) treatment outcomes by better optimizing the use of the chemotherapy drug asparaginase. Asparaginase is a bacterial enzyme and is an indispensable drug in curing pediatric ALL. However, this drug has a strong propensity to induce the formation of anti-asparaginase antibodies in patients. Anti-asparaginase antibodies neutralize the drug’s activity and reduce drug exposure. This reduced drug exposure to asparaginase compromises its anti-leukemic efficacy and increases the risk of leukemia relapse. However, no effective strategy currently exists to prevent the formation of anti-asparaginase antibodies. Given the essential role of asparaginase in curing pediatric ALL, there is a critical need to identify effective strategies to prevent the development of anti-asparaginase antibodies. Our research group in preliminary murine studies has identified that repurposing dipyridamole, an FDA approved antiplatelet drug, can prevent the formation of anti-asparaginase antibodies and restore asparaginase activity and efficacy. We hypothesize that dipyridamole suppresses anti-asparaginase antibodies by increasing the concentration of the endogenous immunosuppressive compound adenosine. The next steps of this project are to test these mechanistic hypotheses, with the ultimate goal of determining whether the adenosine signaling pathway can be modulated to prevent anti-asparaginase antibodies and restore asparaginase efficacy in the treatment of pediatric ALL.”

 

Madeline Lipp, University of Pittsburgh, Herb and Nina Demuth Award

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.”

 

Autumn McKnite, University of Utah

Mentor: Dr. Kevin Watt

Research Title: Elucidation of molecular mechanisms of prenatal cannabinoid exposure: Identification of targets and therapies

“Continuous renal replacement therapy (CRRT) is a form of dialysis that is life saving for children with acute kidney injury. Despite this, children supported with CRRT are at still at high risk for death, with mortality rates exceeding 40%.1-7 This high mortality is thought to result in part from altered drug exposure. Altered drug exposure occurs from 1) drug-drug interactions due to the administration of multiple drugs; 2) multi-organ dysfunction; and 3) direct drug interaction and/or removal of drug by the CRRT circuit.8-16 As a result, for most drugs, optimal dosing in children on CRRT is unknown.

The goal of this study is to determine optimal dosing of 5 commonly used drugs in children on CRRT. In AIM 1 we will determine how drugs interact with the CRRT machines by injecting five drugs singly and together into isolated, closed-loop CRRT circuits. In AIM 2 we will build physiologically based pharmacokinetic (PBPK) models to predict optimal drug dosing in children. PBPK models are computational models in which the body is represented as a set of virtual organ compartments linked by blood flow. Mathematical equations characterize changes in drug concentrations as the drug passes through the virtual organs. These mechanistic models can account for the impact of physiologic covariates such as age and disease and incorporate the impact of drug-drug interactions. The data from AIM 1 will be used to build a CRRT “organ” in the PBPK model to account for the impact of CRRT on drug dosing. Finally in AIM 3 we will collect prospective drug concentration data from children who are on CRRT and receiving one or more of the selected drugs. We will compare the observed concentration data from these children with the PBPK model-predicted concentration data in order to refine and validate the PBPK model. We will use the final PBPK model to predict optimal dosing under different scenarios such as drug co-administration and different CRRT settings.”

 

 

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

Kristen Hong, University of Michigan, Second Year Fellow

Mentor: Dr. Anna Schwendeman

Research Title: Optimization of HDL Mimetic Micelle Composition for the Treatment of Atherosclerosis and Thrombosis

“Atherosclerosis and Thrombosis are two diseases that can lead to heart attack and stroke. Currently, medications that are used to treat these potentially fatal diseases have many side effects, and do not reduce the risk of cardiovascular events to a large extent. Therefore, our goal is to develop a more targeted and effective therapeutic to treat these diseases. We have particles in our body called high density lipoproteins (HDL) that are able to move cholesterol from the tissues and to our liver to be eliminated through our waste. Cholesterol buildup is one of the major contributors to the development of atherosclerosis and thrombosis. Therefore, HDL can be beneficial in these diseases by taking the extra cholesterol and removing it from the body. Due to this fact, synthetic HDL (sHDL) have been created by scientists in order to increase the transfer of cholesterol from tissues to the liver for elimination, reducing the development and progression of disease. Unfortunately, sHDL are expensive and difficult to make and this can be off-putting to pharmaceutical companies. This led to the idea to create a HDL mimicking nanoparticle that is more cost-friendly and easy to produce, and is able to have the same therapeutic capabilities as HDL. To mimic HDL, we decided to take the lipid components of sHDL, and remove the one component that makes the particle expensive, proteins, to achieve our micelles. One micelle has shown to have promising ability to remove cholesterol like HDL. We believe that we can improve the efficacy of our micelle by exploring different lipids that make up our micelle particles, which may change it’s activity. My project’s goal is to find a composition of micelles that shows the highest efficacy in treating atherosclerosis and thrombosis in hopes to reduce deaths and the cost burden for patients that suffer from these diseases.”

 

Matthew Hursey, University of Maryland, Baltimore

Mentor: Dr. Sarah Michel

Research Title: Unraveling the physicochemical properties of iron nanoparticle drug, Ferric Derisomaltose, an important drug for treating iron deficiency anemia

“Iron deficiency anemia (IDA) is a condition in which red blood cells are diminished because of lack of iron in the body. In the United States, there are more than 3 million IDA cases each year. The cases can vary, but children and older adults are affected heavily due to inadequate nutritional intake. Patients with other underlying conditions such as type two diabetes and chronic kidney disease are also likely to develop IDA. The incidence of IDA is growing in the US. Fortunately, IDA can be treated with iron supplementation, typically through intravenous (IV) products, and there is a need for additional IV products including generics.

Currently, there are only 8 approved innovator IV products and 2 approved generic products. Developing generic IV products have been difficult due to a lack of standardized equivalence testing and analysis of physicochemical properties. The composition of IV iron products and their active pharmaceutical ingredient is also under debate.

My project goals are to characterize the most recent FDA approved iron nanoparticle drug, Monoferric, and determine its active pharmaceutical ingredients. I will develop novel techniques to characterize the drug that have the potential to become a standard for analyzing current and future nanoparticle drugs. These standards will contribute to the development of future innovator and generic drugs.”

 

Drug discovery/medicinal chemistry

Nicole Bentz, University of Minnesota

Mentor: Dr. Carston Wagner

Research Title: The Fundamental Investigation and Application of a Novel Self-Assembling Peptide in Chemotherapeutic Drug Delivery

“My thesis work focuses on the fundamental investigation and application of Guanosine-Tetrad Self-Assembling Nucloside Phosphoramidate hydrogels. The expected outcomes of my thesis work include the synthesis and characterization of a panel of novel self-assembling nucleoside phosphorates and the hydrogels they form, quantifying the sustained release kinetics of Doxorubicin, and demonstrating the biological advantage of the hydrogel system through in vitro and in vivo efficacy studies. We hypothesize that localized delivery of a Doxorubicin hydrogel depot capable of sustained sensitive release will prolong clearance rates, improve its safety profile, and be more efficacious than delivery of the free drug. The overall objective of my research is to improve the efficacy and safety of the potent chemotherapeutics by establishing a drug delivery system that reduces their off-target effects.”

 

Caroline Buchholz, University of Minnesota

Mentor: Dr. William Pomerantz

Research Title: Chemical Probe Development for Bromodomain and PHD Finger-containing Transcription Factor (BPTF) for Anti-Cancer Therapy

“Epigenetics is the study of mechanisms that result in differential gene expression without changes to the underlying DNA. Epigenetic regulation leads to differential activation and repression of genes that can lead to cellular differentiation in healthy cells. However, alterations in these mechanisms can lead to disease state. My project aims to better understand the role of an epigenetic protein, BPTF (bromodomain and PHD finger-containing transcription factor), in disease states. While BPTF has been implicated in numerous cancers, the role of specific domains (bromodomain, plant homeodomains) in BPTF are largely unknown. My project goals are to rationally design chemical probes and evaluate their inhibitory effects in cancer cell lines to elucidate the mechanisms of BPTF in the disease state.”

 

Christopher Stevens, University of Wisconsin-Madison

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.”

 

Holli-Joi Sullivan, University of North Carolina at Chapel Hill

Mentor: Dr. Alexander Tropsha

Research Title: Computer-aided discovery and validation of broad-spectrum antiviral agents for emerging viruses

“The emergence of SARS-CoV-2 demonstrates the detrimental effects of new viral emergence events on global human health and the economy. New viral emergence events are increasing: in the 21st century alone we have experienced ~13, several of which caused significant human morbidity and mortality. Many of these, very different, virus families have similar drug binding sites critical to their function. Thus, my hypothesis is that developing antiviral compounds targeting these conserved binding sites may lead to the identification of compounds with activity against multiple viruses. My preliminary results indicate that there is a potential for such compounds to be identified by tracking coincidences in literature, and I feel that systematic, coordinated efforts to generate potent antivirals that are active against multiple viruses could be a powerful response strategy to both existing and future emerging viral threats.”

 

Nicholas Young, University of California, San Francisco

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)

Gerrit Vreeman, University of Minnesota, Dr. Paul B. Myrdal Fellowship

Mentor: Dr. Changquan Sun

Research Title: Structural origin of mechanical properties and tableting behaviors of elastically bending pharmaceutical crystals

“Tablets are the most popular solid oral dosage form because they are inexpensive and easy to manufacture, have high stability, and have high patient compliance. Developing formulations that can robustly produce high-quality tablets is often a lengthy process in the traditional drug development process, which relies on a trial-and-error-based approach. This approach often results in process scale-up failures or manufacturing problems due to factors such as batch-to-batch variations of active pharmaceutical ingredients (APIs) or excipients, leading to drug shortages. Therefore, understanding an API’s key material attributes, mechanical properties, and powder mechanics is essential to design quality into pharmaceutical tablets.”

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

Matthew Le, The University of Texas at Austin, Second Year Fellow

Mentor: Dr. Maria Croyle

Research Title: Analytical Characterization of Viscosity and Moisture Content in a Thermostable Film

“The goal of this project is to improve upon a dissolvable film platform, which can deliver drugs or vaccines through the mouth.  This film is like a Listerine breath strip, where it can be placed inside the cheek or under the tongue and be easily dissolved.  This film has a much smaller packaging footprint compared to traditional vaccines, and it can be stored at room temperature.  This eliminates or reduces the logistical needs for refrigerators and freezers.  To improve the technology, I am studying how moisture content within the film impacts its stability.  I am also studying a variation of the film which can be easily dissolved in an IV bag, so that it can be used with existing IV therapies.”

 

 

Warren Smith, Auburn University, Second Year Fellow

Mentor: Dr. Vishnu Suppiramaniam

Research Title: Elucidation of molecular mechanisms of prenatal cannabinoid exposure: Identification of targets and therapies

“Alzheimers disease (AD) kills more people every year than prostate and breast cancers combined, but no new medications for AD have been approved by the FDA in over 15 years. Obesity and diabetes both increase the risk for developing AD, while healthy diets and lifestyle modifications decrease this risk. Recently, a hormone called amylin, which is released alongside insulin in the body to help control our blood sugar and how much we eat, has gained attention as a possible therapy for AD. However, we must first determine if amylin is beneficial in AD due to direct effects on the brain or due to its effects on diet and metabolism. Our project aims to distinguish between the direct and indirect effects of amylin-based therapy in AD and to provide evidence for an intranasal amylin-based therapy as a future treatment for AD.”

 

Social and Administrative Sciences

Madeline Brendle, University of Utah, ASHP-AFPE Fellowship

Mentor: Dr. Dan Malone

Research Title: Real world evaluation of the effectiveness, safety, cost of care, and barriers/motivations for adoption of esketamine and ketamine as pharmacotherapies for mental health conditions

“The goals of my project are focused on evaluating the effectiveness, safety, cost of care, and barriers/motivations for the adoption of esketamine and ketamine as pharmacotherapies for treatment-resistant depression (TRD) and other psychiatric conditions in real-world clinical practice. Ketamine is a dissociative anesthetic traditionally used as an anesthetic and analgesic agent. However, at sub anesthetic-doses, ketamine has been observed to have dissociative/hallucinatory effects that have led to rapid and significant improvements in depression and other mental health conditions.1-4 While racemic ketamine is only prescribed for psychiatric disorders as an off-label indication, esketamine nasal spray (SpravatoTM) was developed as a rapid-acting treatment for TRD and major depressive disorder (MDD) with acute suicidal ideation.5,6 Both esketamine and ketamine have garnered interest with their novel mechanism of action for depression pharmacotherapy and rapid reduction of depressive symptoms as early as 24 hours post-administration of the medication.2,4,5

I aim to increase the knowledge base of ketamine and esketamine as treatments for TRD and other mental health conditions in real-world clinical practice. Esketamine and ketamine are fundamentally changing how researchers and clinicians study and treat psychiatric disorders. By conducting this important work, researchers, clinicians, and patients can better understand the long-term and real-world benefits, risks, affordability, and accessibility of esketamine and ketamine treatment for mental health conditions.”

Daniel Dauner, University of Minnesota, AFPE Regional Award

Mentor: Dr. Joel Farley

Research Title: Optimization of Signal-Detection Algorithms in Novel Databases: a Focus on Direct-Acting Antivirals

“Signal detection algorithms are statistical methods used to identify safety signals in adverse drug event databases. My dissertation will focus on applying subgroup analysis and developing a predictive model to increase the performance of signal detection algorithms.  Subgroup analysis is an epidemiologic technique and is important because a drug may be associated with an adverse event in a specific subgroup despite not showing an overall association.  Machine learning will be used to develop predictive models to help identify signals and prioritize which ones need further clinical review.”

 

Sarah Khor, University of Washington, Pre-Doctoral Fellowship in Health Outcomes Disparities

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.”

 

Tyler Wagner, Virginia Commonwealth University, Second Year Fellow

Mentor: Dr. Teresa Salgado

Research Title: Predictive and Pharmacoeconomic Modeling of Pharmacy Services in Primary Care

“Primary care is facing a physician shortage, with a projected shortage of between 21,100 and 55,200 physicians by 2032. In 2016, Americans made nearly 490 million primary care visits, a number expected to continue to rise due to an aging population and projected population growth. More and more research has shown that pharmacists, when involved in patient care teams, can effectively manage chronic disease management. Our project aims to analyze patient data from a local health system to determine what characteristics – whether social, demographic, or clinical – contribute to a patient not achieving optimal patient outcomes or quality measure achievement. An example of quality measure achievement in hypertension is reducing a patient’s blood pressure to < 140/90 mmHg or in diabetes, reducing a patient’s hemoglobin A1c% to < 9% or lower. Quality measures are rooted in appropriate disease state management and are a way for health plans or health systems to determine how well they are providing care for their patients. We plan to take these identified characteristics to develop a referral tool for health systems, allowing them to more readily identify patients that could benefit from additional care from a pharmacist. Second, we want to identify any health disparities that exist within the data to better address gaps in care. Literature from the Centers for Disease Control and Agency for Healthcare Research and Quality have shown that patient care and associated outcomes can vary significantly by racial and ethnic groups, by sex, and by insurance status. Lastly, we plan on analyzing the cost of staffing pharmacists within primary care clinics and will compare the outcomes of patients from clinics with pharmacists to the outcomes of patients from clinics without pharmacists. We aim to determine if pharmacists within primary care provide value and if so, are they affordable.”