Summer Undergraduate Research Program (SURF)

William E. Fantegrossi, Ph.D.

Behavioral pharmacology of emerging drugs of abuse

Email: WEFantegrossi@uams.edu

Clandestine chemists are continually synthesizing New Psychoactive Substances (NPS) for illicit use. In most cases, these NPS are chemical analogs of established drugs of abuse, but small changes in chemical structure can result in large changes in pharmacological activity and in toxicity, often in unpredictable ways. My laboratory is currently working with several categories of these drugs, including synthetic cannabinoids (constituents of K2/“Spice” smoking blends), analogues of cathinone (present in “bath salts” preparations), designer opioids (analogs of fentanyl), emerging psychedelics and entactogens, and novel arylcyclohexylamines (related to PCP and ketamine.) In an effort to better understand both the abuse-related and potential therapeutic implication of NPS, we use a wide range of behavioral and physiological tests in rodents, and compare the actions of these novel compounds to those of more well-known drugs from the same pharmacological classes. Students interested in working in my lab will have the opportunity to assist with surgeries, work with intact, behaving mice and rats, and assist with sample collection for studies involving tissue distribution and disposition of drugs. My laboratory integrates the basic sciences of chemistry, pharmacology, experimental psychology and biology, as well as the clinical application of these scientific discoveries. Students will thus be able to choose among specific experiments that can be matched to their background and interest. Students with biology, chemistry, neuroscience or psychology backgrounds are particularly encouraged to apply.

Alexei Basnakian, M.D., Ph.D.

Role of DNA endonucleases in kidney injury

Email: BasnakianAlexeiG@uams.edu

The main area of research of Dr. Basnakian’s laboratory is endogenous cytotoxic DNA endonucleases (DNases), which damage and destroy DNA. Cell death is commonly associated with the enzymatic fragmentation of DNA. Cells have excessive DNA-degrading power provided by the group of cytotoxic DNases/endonucleases which includes: DNase I, DNase II, caspase-activated DNase, endonuclease G, DNase gamma and several other enzymes. Sometimes these enzymes are called “apoptotic endonucleases,” however they participate in necrosis, necroptosis, ferroptosis, mitotic catastrophe, and other modes of cell death. Other roles of cytotoxic endonucleases include clean-up after cell death, removal of foreign DNA inside the cell, and cleavage of DNA circulating in plasma and other body fluids. Normally, host cell DNA is protected against these DNases. However, during a toxic cell injury or disease, genomic DNA becomes accessible to cytotoxic endonucleases due to the change of cellular homeostasis and increased permeability of membranes. Students in Dr. Basnakian’s lab will learn to study endonucleases in the renal tubular epithelium during ischemic or toxic acute renal failure. Other projects include studying endonucleases in liver cells during acute toxic injury, in heart during hypoxia-reoxygenation, or in cancer cells during chemotherapeutic drug-induced apoptosis. No matter which project is chosen, students will gain experience in a number of biochemical, histology, and microscopy techniques.

John Imig, Ph.D.

New treatments for kidney and cardiovascular diseases

Email: JImig@uams.edu

Research in the laboratory focuses on kidney and blood vessel function in normal and disease states. We have developed novel drugs to treat diseases including hypertension, stroke, heart attacks, metabolic diseases, diabetes, and kidney diseases. We have three major research projects ongoing in the laboratory. (1) Obesity, hyperlipidemia, fatty liver disease, hypertension, and type 2 diabetes are major contributing factors to the increase in the number of patients that have cardiovascular events and end-organ damage. The laboratory is developing and testing drugs that have two activities to treat diabetes and metabolic disorders. (2) Our laboratory has identified and developed epoxyeicosatrienoic acid (EET) analog drugs that show promise as a novel therapeutic approach for kidney diseases. EET drugs have renal anti-inflammatory, anti-apoptotic, and anti-oxidative activities that will translate into a novel therapeutic. We have recently developed a kidney targeted EET drug. Consequently, we will test kidney targeted EET drugs as a new and better treatment for kidney diseases. (3) Fructose consumption has increased dramatically in recent decades due to the use of high-fructose corn syrup and has been implicated in obesity & salt-sensitive hypertension. The increased consumption of high-fructose containing sodas and processed foods has been strongly implicated in the epidemics of hypertension, type 2 diabetes, obesity, and renal failure. This project will determine the association of dietary fructose with blood pressure salt-sensitivity in animal models and human subjects to determine renal microvascular mechanisms by which fructose intake affects blood pressure and kidney disease.

Kyounghyun Kim, Ph.D.

Precision medicine approaches to develop new drugs targeting nuclear receptors for treatment of liver diseases and cancer

Email: KKim@uams.edu

About 16% of FDA-approved drugs target nuclear receptors (NRs), like estrogen receptors, acting as a molecular switch to delay human diseases and cancers. Our lab first focuses on exploring novel roles of nuclear receptor NR2E3 in liver diseases and cancer using NR2E3 knockout mouse models and a single-cell RNA seq approach. Our current studies aim to understand NR2E3’s role as a tumor suppressor, potentially leading to its use as a prognostic marker or therapeutic target in liver diseases and cancer. Secondly, N6-methyladenosine (m6A) is a critical mRNA modification in eukaryotes, influencing mRNA stability, splicing, transport, and translational efficiency. Using Nanopore long-read sequencing and transgenic animal models, we are investigating the role of m6A signaling in tissue injuries and cancers induced by carcinogens. Understanding m6A modifications in these contexts will fill a scientific gap in knowledge and lay a foundation for developing improved treatments. Thirdly, long noncoding RNAs (lncRNAs) are RNA molecules over 200 bp long that do not encode proteins. We have identified many lncRNAs associated with pro-oncogenic transcription factors (TFs). Since lncRNAs can be targeted therapeutically, characterizing the roles of lncRNA-TF interactions will provide a novel insight for pancreatic cancer treatment.

Ricky Leung, Ph.D.

Endocrine disruptors and cancers

Email: RickyLeung@uams.edu

Hormone-based therapy remains the most viable option for treating prostate and breast cancer patients. It is crucial to understand how exposure to environmental endocrine disruptors (EDCs) would interfere cancer growth and promotion. EDCs are ubiquitous and are capable of interfering normal hormone signaling at different levels but their downstream molecular mechanisms remain largely unknown. Our laboratory employs multiple genome-wide approaches to identify key pathways, instead of focusing on traditional one-gene one-target approach. We found that EDCs like environmental estrogens could pose much greater risk to human health than other classical toxicants as the dose required to elicit changes can be minimal. We are currently studying the endocrine-disrupting effects of metals and determine their underlying molecular changes in multiple mouse models. Some of these changes can be stable throughout life and transmissible to more than one generations. Our long term goal is to understand the impact of EDCs on cancer etiology and therapeutics as well as look for biomarkers for monitoring exposures and/or for assessing the underlying cancer susceptibility. Students with strong interest in molecular biology/toxicology/endocrinology and cancer biology are encouraged to apply.

Jeffery H. Moran, Ph.D.

Analytical toxicology requirements for opioid testing

Email: JHMoran@uams.edu

In 2022, the Centers for Disease Control (CDC) and the United Nations estimated that 1.2% of the world population misused opioids and greater than 70% of overdose deaths worldwide involved opioids. Solving the opioid epidemic is complex because many different types of opioids are publicly available, and the potency of natural, synthetic, and mixed formulations vary greatly. The epidemic has reached a point where physicians, public health officials, poison control centers, and law enforcement no longer have the most basic information necessary to perform their jobs. To be effective in saving lives and educating communities, first responders and front-line professionals need to know exactly which opioid drugs are present in an overdose victim, in real time. Quantifiable, precision testing is a foundational step to preventing and treating the harmful effects of opioid use disorder. My research focuses on the development and validation of revolutionary toxicology capabilities to refine early detection techniques to detect opioids, including newer synthetic opioids which often escape detection. We collaborate with communities and local, state, and federal agencies across the US to implement comprehensive opioid surveillance programs and to define what opioids are circulating in black markets. Our efforts lead to increased clinical and forensic testing and enable out partners to detect opioids in human specimens. Data facilitates multiple research strategies that sharpen analytical approaches to combat this devastating epidemic. Our translational research efforts form the foundation for better treatments and community-based intervention programs.

Andrew Morris, Ph.D.

Lipid metabolism and signaling in cardiovascular disease

Email: AJMorris@uams.edu

My laboratory studies lipid metabolism and signaling in cardiovascular disease. A particular focus is on the PLPP3 gene which is associated with heritable risk of cardiovascular diseases that includes coronary artery disease and calcific aortic valve disease. The gene functions as a suppressor of experimental atherosclerosis and valve calcification in mouse models. PLPP3 is essential for formation of blood vessels in the developing mouse and controls the plasticity of cells in the adult animal that drive changes in the blood vessels and heart valves that are central to the development of cardiovascular disease. To study the underlying mechanisms, we have made human inducible pluripotent stem cells with homozygous inactivation of the PLPP3 gene. These cells can be differentiated to different cell types in vitro which allows us to study the impact of PLPP3 deficiency on this process and to generate differentiated cells that lack PLPP3 to study their phenotypes. We expect that this approach will shed light on the role of PLPP3 in development and cardiovascular diseases and identify the underlying mechanisms involved. A student working in the laboratory on this research would learn about cell culture, biochemical and molecular biological techniques including light microscopy. Exposure to chemicals in the environment is a recognized determinant of human non communicable disease risk. Perfluorinated alkyl substances (PFAS) are manmade surfactant chemicals with widespread uses that are highly persistent and can be detected in the blood of almost all adult Americans. Our laboratory uses advanced analytical methods to monitor exposure to these chemicals to support large population health studies. These include studies of PFAS exposure in Veterans and Service Members and studies of how maternal PFAS exposure impacts on early child development. We are also developing simple approaches to enable expanded testing for PFAS by using self-administered blood microsampling methods. A student working in the laboratory could participate in a clinical study to compare PFAS levels in microsampled whole blood and venous blood from veterans receiving care at the Central Arkansas VA healthcare system. The student could learn about clinical research and about the mass spectrometry based analytical methods we use to test for these chemicals.

Shengyu Mu, M.D., Ph.D.

Pathogenesis of hypertension and cardiac dysfunction

Email: SMu@uams.edu

Our laboratory is dedicated to research aimed at understanding the pathogenesis of hypertension and cardiac dysfunction. Our primary focus centers on elucidating the important role of immune disorders in driving the development of hypertension and cardiovascular diseases. Our ongoing research includes the following key areas: 1) Investigating the mechanisms underlying the inappropriate activation of T cells that infiltrate the kidney, stimulating sodium transporters, promoting salt retention, and consequently elevating blood pressure. This project also explores potential treatments to modulate these mechanisms. 2) Unraveling the pathogenic roles of T cells and macrophages in promoting cardiac diastolic dysfunction as hypertension progresses. We aim to elucidate the underlying mechanisms and contribute to a deeper understanding of this condition. 3) Probing the molecular mechanisms linking the pathogenesis of diabetes with the development of hypertension and the promotion of metabolic syndrome. This research seeks to identify critical molecular pathways involved in this process. Our laboratory projects are continuously funded by AHA Beginning Grant in Aid award, NIH R01 funding, AHA Transformational Project Award, and several internal research funding channels. We have garnered extensive expertise in conducting both in vivo and in vitro experiments and accumulated comprehensive background knowledge in the research fields of physiology, molecular biology, pathophysiology, and immunology.

Nirmala Parajuli, Ph.D.

Improving kidney outcomes after transplantation by understanding mechanisms for damage induced by cold storage

Email: NParajuli@uams.edu

Optimizing long-term kidney graft function continues to be a challenge, especially with kidneys from deceased donors, which comprise 70% of total transplants. One key variable between living and deceased donors is preservation using cold storage (CS)—kidneys from deceased donors undergo CS for preservation, while kidneys from living donors are generally excluded from or minimally exposed to CS. Unfortunately, prolonged CS (≥ 4 h) is detrimental to graft function after transplantation. This highlights the importance of preventing the triggers of CS-related injury, especially because more than 20% of donor kidneys are discarded or not transplanted each year in part due to CS-mediated tissue injury. Therefore, long-term interest of the Parajuli Lab is to investigate novel mechanisms by which CS induces injury in the kidney grafts leading to the identification of novel therapeutic targets that could lead to improved kidney outcomes after transplantation. The Parajuli Lab has established a rat kidney transplantation model, which will be fundamental in studying mechanisms of kidney injury and testing therapeutics during transplantation. Specifically, the research team is investigating the roles of proteasome, heat shock proteins, and complement pathways during kidney CS plus transplantation. Decreasing the injury associated with CS could help organs be used more effectively, delay graft failure, improve long-term graft survival, and lower the mortality rates for patients with end-stage kidney disease.

Paul L. Prather, Ph.D.

Characterization of intracellular CB1 receptor signaling mechanisms in response to acute and chronic exposure to synthetic cannabinoid receptor agonists and their metabolites

Email: PratherPaulL@uams.edu

K2 or Spice products are forms of “fake pot” that are most often abused by smoking inert dried plant material laced with a mixture of various synthetic cannabinoid receptor agonists (SCRAs). These compounds produce psychotropic actions similar to ∆9-THC, the major active ingredient found in marijuana, by activating cannabinoid type 1 receptors (CB1Rs) in the brain. However, unlike the relatively “safe” actions of marijuana, use of products containing SCRAs results in a number of adverse effects that are more severe and distinctly different than those produced by ∆9-THC. We have reported that several metabolites of a number of different SCRAs retain both high affinity and activity at CB1Rs and thus might contribute to the toxicity experienced by abusers following use of these compounds. In addition to acute adverse effects, chronic SCRA abuse results in development of greater tolerance and physical dependence relative to similar extended use of marijuana. Therefore, this project will characterize both acute actions and effects of chronic exposure to emerging SCRAs and their metabolites on intracellular signaling of CB1 receptors in cellular models, compared to ∆9-THC. Understanding acute signaling mechanisms and adaptations in CB1 receptor signaling in response to prolonged SCRA exposure should aid in development of novel therapeutic strategies to mitigate the toxic effects resulting from use of these drugs of abuse.

Nancy J. Rusch, Ph.D.

Ion channel function in cardiovascular disease

Email: NRusch@uams.edu

My laboratory has explored the mechanisms of pulmonary and systemic hypertension for more than three decades with a special interest in the action and therapeutic effects of medications that act on calcium and potassium channels to modulate blood pressure and blood flow. Calcium and potassium channels conduct Ca2+ and K+ ions, respectively, across the surface membrane of vascular muscle cells. Abnormalities in these channels trigger contraction of small arteries resulting in high blood pressure (hypertension). The goal of our laboratory is to discover abnormalities of ion channel expression and composition that contribute to systemic and pulmonary hypertension, and identify channel-based therapies to treat these diseases. We employ a multi-faceted approach of patch-clamp, molecular, cellular and in-vivo techniques to accomplish this goal. Projects conducted in my lab have helped to resolve the question of why calcium channel blockers dilate arteries but not veins, and the question of why this family of commonly used drugs effectively lower blood pressure in hypertensive subjects but have little antihypertensive effect in subjects with normal blood pressure. More recently we have investigated the mechanisms by which potassium channel openers (KCOs) activate KATP channels in lymphatic muscle cells, which may explain the peripheral edema that is an off-target effect of these medications. This project was performed, in part, by two former SURF students who were co-authors on relevant publications. My training focus at this mature stage of my career is teaching electrophysiology to interested trainees with an emphasis on whole-cell and single-channel patch-clamp of vascular cells for detect ion channel abnormalities in disease and/or uncover mechanisms of drug action.

Amanda Stolarz, Ph.D.

Ryanodine Receptors as Therapeutic Targets to Prevent Doxorubicin-Induced Lymphatic Dysfunction

Email: AStolarz@uams.edu

Dr. Stolarz’s laboratory is focused on learning the techniques and approaches that underscore hypothesis-driven basic and translational cardiovascular/lymphatic pharmacology research. The primary focus is the mechanisms of damage to the lymphatic system during cancer therapy and developing therapeutic strategies to reduce this damage. The laboratory uses the techniques such as tissue dissection, enzymatic cell isolation, flow cytometry, vascular functional studies, and gene and protein expression assays. The laboratory also administers pharmacological agents to animals and employs both non-survival and survival surgical techniques to measure lymph flow in vivo. In addition, critical review of scientific literature is highly encouraged. Dr. Stolarz’s laboratory is highly collaborative with other laboratories in the UAMS Department of Pharmacology and Toxicology and makes use of the Flow Cytometry and Genomics Core facilities located within UAMS.