2023-2024 Gateway Awardees

Xiaoying Huang, University of California, San Diego

Mentor: Dr. Palmer Taylor

Research Title: Balanced Central and Peripheral Activating Antidotes to Organophosphate Pesticide Exposure

“This project of developing an antidote to an organophosphate pesticide is similar in design to developing a unique therapeutic agent.  Since the toxic organophosphate, such as sarin or soman or a pesticide (chlorpyrifos), is a neutral compound, we plan to develop an antidote or antidote-transport inhibitor combination that will distribute into the central as well as the peripheral nervous system.  Through in vitro and cell culture studies, we have found that RS194B, with its aldoxime moiety and azepine ring, is a superior zwitterionic antidote of nearly 100 congeners synthesized and ranked by the Taylor-Sharpless group.  Accordingly, a similar comparison will be made for tariquidar, an agent under clinical trials for resistant breast cancers, and the fluoroquinolone antimicrobials which are also zwitterionic agents.  Hence, we have selected a primary zwitterionic antidote, ionizing with positive, negative, zwitterionic, and neutral forms, we found it ranked superior amongst 100 candidate agents in terms of its target site selectivity.  Since the blood-barrier affords a dual protection by (a) being selective for the neutral or uncharged ionization state and (b) by extrusion transport by a transporter found in the membrane between the capillary lumen and the brain or CNS extracellular fluid, we use the combination of an ionizing antidote with an amine conferring the positive charge and the oxime conferring the negative charge.  Hence, our antidotal combination should enable balanced antidotal activity in the central and peripheral nervous systems. Our approach equates central and peripheral nervous system activity, and provides a comprehensive antidotal activity that now should surpass the FDA-approved antidote 2-PAM. The latter quaternary antidote, 2-PAM, poorly or slowly crosses the blood-brain barrier.”

 

Clare Johnson, University of Kentucky

Mentor: Dr. Daniela Moga

Research Title: The Prevalence of Substance Use Disorder in Transgender Adults Over the Last Decade

“This project aims to understand the rates of substance use disorder (SUD) in transgender adults over the last 10 years. The student hypothesizes that the rate of substance use disorder diagnosis (SUDD) in the transgender adult population has risen over the last decade, due to increased visibility of transgender adults and greater awareness of transgender issues. Members of minority groups are more likely to experience additional stressors, such as discrimination, violence, and internalized stigma. Sexual and gender minorities also have a higher likelihood of engaging in risky behaviors, including sex work, which can contribute to substance abuse. Therefore, it is crucial to understand the rates of SUD among the transgender population and develop tailored interventions that address their specific needs. For this project, the student will be utilizing data from Truven MarketScan, an administrative database that contains de-identified information from commercial healthcare claims. Since data on gender identity is not captured in these claims, they will use an established algorithm to identify transgender adults in claims data. Using this data, the student will analyze the prevalence of SUDD in transgender adults as compared to cisgender adults for every year from 2010 to 2020. Additionally, they will investigate prevalent substances of abuse in transgender versus cisgender adults, and rates of related diseases such as HIV and Hepatitis C in adults with a diagnosed SUD. We anticipate that the size of the population will be underestimated due to the lack of gender identity data in claims, therefore, the impact of our findings will likely be larger. By shedding light on the burden of SUD among this population, this project aims to contribute to the existing research on the need for gender and sexual minority-specific SUD treatment programs.”

 

Andrea Pence, University of California, San Diego

Mentor: Dr. Anthony O’Donoghue

Research Title: Targeting the Naegleria fowleri Proteasome for Treatment of Primary Amebic Meningoencephalitis

“Primary Amebic Meningoencephalitis (PAM) is a rare brain infection that is caused by a brain-eating ameba known as Naegleria fowleri.  This infection occurs when individuals are swimming in contaminated pools, lakes, and reservoirs. The parasite in the water enters the brain via the nostrils and causes symptoms similar to bacterial meningitis. However, the infected person almost always dies within one week. Treatment of patients with current drugs have severe side effects and many still do not survive. We have discovered that a currently approved cancer drug called bortezomib (marketed as Velcade), quickly kills the parasite when growing in the lab. In this project, we aim to show that mice infected with this parasite can be cured using bortezomib. In addition, we will determine if bortezomib directly targets an enzyme in the parasite, called proteasome. The longterm goal of this project is to evaluate if bortezomib can be used to treat patients infected with this brain-eating ameba.”

James Sagun, University of Texas at Austin

Mentor: Dr. Maria Croyle

Research Title: Determining the Antimicrobial Effectiveness of a Novel Pharmaceutical Excipient within Oral Thin Films

“The Croyle Lab discovered a way to preserve vaccines in a thin film in a manner that allows them to be shipped and stored at room temperature without the need for ice and refrigeration.  This film, which looks like a Listerine breath strip (Figure 3), is made of sugars, cellulose and a novel compound which that is responsible for preserving vaccines and improving how they work in the body.  Even though they contain sugar, the films have not been shown to develop mold or bacterial growth for 3 years.  This project will test the ability of the novel compound alone or in combination with each film component to prevent or slow the growth of bacteria using a test recognized as an industry gold standard by the FDA.  Results from this project will be important to drug development as use of this compound could extend expiration dates and prevent spoilage and waste of expensive vaccines and other biologic drugs. ”

 

Lauren Thompson, University of Utah

Mentor: Dr. Aaron Wilson

Research Title: Comparison of DOAC Treatment Strategies for Secondary VTE Prophylaxis

“We plan to conduct a retrospective cohort study to describe long-term prophylaxis strategies for patients who have already experienced venous thromboembolisms (VTEs). Current recommendations suggest that continuation of anticoagulation is indicated in certain populations. These include patients experiencing unprovoked VTEs, cancer, prothrombophilic disease states, and unresolved VTE risk factors. First line therapy for the treatment of these VTEs consists of using direct oral anticoagulants (DOACs) at specified dosing. Despite the clarity for initial treatment level dosing, guidelines are less clear regarding long-term (>6 month) prophylaxis. We will be comparing patients who are indicated to recieve long-term, secondary prophylaxis and who are taking DOAC medications. Primarily we will compare patient demographics, disease state characteristics, and adverse outcomes (e.g., VTE recurrence, bleeding, and death) between patient cohorts of those who maintain treatment level DOAC dosing and those who are reduced to prophylactic level dosing.”

 

Ben Zalupski, Ferris State University

Mentor: Dr. Tracey Ward

Research Title: The Synthesis and Evaluation of Promising PPAR Agonists for Improving Alzheimer’s Disease Pathologies

“The project being proposed to the Gateway to Research Award review committee would encompass refining a current lead compound that has previously shown in past research to be very promising with the treatment of Alzheimer’s Disease (AD). AD is characterized by hallmark features such as memory loss, difficulty completing previously simple tasks, and difficulty with speaking or writing. There is a critical need for new drugs in the pipeline to treat AD pathologies as current drugs on the market, such as Donepezil, Memantine, and Galantamine, will only delay the symptoms and/or progression of disease for 6-12 months. As a result, current drugs do nothing to reverse the AD progression, eventually leading to the disease taking hold. The compounds we have generated so far work in a different way from the other drugs on the market, and therefore have shown to actually improve and reverse neurodegeneration, the mechanism in which Alzheimer’s causes symptoms in patients, in an AD animal model. Data has also shown that behavioral effects improved which is also quite problematic in patients diagnosed with AD. None of the currently available drugs on the market do this so these compounds offer great promise as potential alternatives to treat AD. Previously produced research data from my laboratory has treated an early generation lead compound in an AD induced mouse model, and we were able to show reversal of AD symptoms with only 30-day treatment. It improved both short and long-term memory, and also improved neurotransmission. The focus of this proposed project is to make changes to our previous lead molecule to optimize it’s effect, by binding within the PPAR receptor site, which is the receptor associated with anti-AD effects with the symptoms listed above. By doing so, it is believed this optimization will generate a superior drug candidate. We will test this by developing 3 molecules with better binding for the target and then testing them in brain cells to measure effectiveness and improvement of AD pathologies. We will use computer molecular modeling, basic chemical synthesis techniques and then we will evaluate these lead molecules on brain cells in culture to measure their effectiveness at binding to desired target, improvement of neuroinflammation, and effectiveness in improving AD pathologies. The desired result will be to generate one superior lead molecule that may then be tested in another Alzheimer’s induced animal mouse model to show drug candidate effectiveness at given concentrations. Identification of new lead drug candidates to treat AD is so critically needed in our society as current therapies do not reverse the disease and do not offer the level of therapy to reverse and treat this progressive disease.”

 

Xinge Zheng, California Northstate University

Mentor: Dr. Islam Mohamed

Research Title: miR-146a; a Potential therapeutic modality against shear stress-induced vascular inflammation & atherosclerosis via inhibition of the pro-inflammatory and pro-proliferative Osteopontin pathway.

“Heart attacks stroke and other vascular diseases are usually the result of stiffening of major blood vessels which supply these essential body organs. Stiffening of major blood vessels occurs due to inflammation of blood vessels, which has been found to be directly related to the nature of blood flow that occur in specific areas of blood vessels. Using a simple analogy of a “water hose” to describe blood flow; If the blood flow occurs in one direction with high speed, the blood vessels stay healthy with minimal stiffening. Vice versa, when blood flow is is turbulent in nature and lower in speed, then the blood vessel becomes inflamed, which is the first step needed to develop the blood vessel stiffness. Within the blood vessel tissues, there are specific molecules that are responsible for responding to these mechanical changes in blood flow. Of these molecules, our research group is interested in studying a specific molecule that is called micro-RNA146a (miR-146a). High levels of miR-146a are found in areas of blood vessels that are subjected to the healthy kind of high speed, one direction blood flow. Which in turn, can suppress the inflammatory molecules in the blood vessel wall and keep it healthy. On the other hand, Osteopontin (OPN), was also found to be one of the major molecules responsible for promoting inlflammation and stffness of blood vassesls. Therefore, our group is interested in studying two research goals: (1) whether high levels of miR-146a, can supress OPN and hence protect against inflammation of blood vessels. (2) whether supplying back high levels of miR-146a to areas of turbulent flow in blood vessels using specific carriers can be used as a tool to treat inflammation and stiffness of blood vessels. In order to study research goal (1), our group will study endothelial cells isolated from human aorta and artificially cultured in the lab in a circular dish. These endothelial cells will be shaked in a circular motion to simulate two areas of blood flow: High speed area at the edges of the cell culture dish, versus, turbulent area with low flow speed in the center of the dish. Afterwards, cells will be studied to determine the levels of miR-146a, OPN and inflammation, and evaluate whether treatment of endothelial cells with high levels of miR-146a can suppress OPN and inflammation in the turbulent flow areas. In parallel, In order to study research goal (2), laboratory mice will be subjected to a unique surgery to induce a localized area of turbulent flow in their aorta by making a slight constriction in it using a specially designed clip. As a result, the aorta tissue becomes more inflamed and lower levels of miR-146a are expected, compared with the other healthy areas with normal blood flow. Afterwards, these mice will be treated with specific carriers that can deliver high levels of miR-146a to the specific areas of turbulent flow of the aorta, then we will evaluate the remaining levels of OPN, inflammation and stiffness in these treated blood vessels.”