Jung Han Kim, PhD Project 1 Project 2

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1 Jung Han Kim, PhD Professor Joan C Edwards School of Medicine at Marshall University rd Ave, 435 BBSC Huntington, WV Tel: (304) kimj@marshall.edu My long-term research interest is in understanding the etiology and mechanisms underlying obesity and Type 2 diabetes, concomitantly related diseases, which have strong implications for cardiovascular diseases. Multiple projects are in progress in my laboratory. Project 1 is to investigate a link between obesity and diabetes and neural and behavioral phenotypes in TALLYHO mice. This project is in collaboration with Dr. Larry Grover, a neuroscientist in our department. The TALLYHO mouse is a polygenic model for human obesity and type 2 diabetes and characterized by increased adiposity, insulin resistance, hyperglycemia, and hyperlipidemia. Students for the summer program will measure rota-rod performance, grip strength, and anxiety-related traits in TALLYHO and C57BL/6 mice fed nutritionally modified diets and molecular characterizations of potential candidate genes. Project 2 is to investigate the effects of bioactive compounds in reducing obesity and diabetes. With the rise in obesity and diabetes in humans, the search for effective interventions has been an active area of research. Among these, use of bioactive compounds and dietary supplements has become an attractive intervention due to their anti-inflammatory, lipid lowering and antioxidant effects. Students for the summer program will measure fat mass, energy intake and expenditure, and inflammation markers in TALLYHO and C57BL/6J mice fed high fat diets supplemented with and without bioactive compounds.

2 Wei Li, MD, PhD Associate Professor Joan C. Edwards School of Medicine Marshall University 1 John Marshall Drive, Huntington WV Phone: Fax: liwe@marshall.edu Projects summary Dr. Wei Li laboratory is studying thymidine phosphorylase (TYMP), an intracellular enzyme, on development of cardiovascular diseases. Project #1 is to study the role of TYMP on activation of platelets, one type of small circulating cells, which prevent blood loss when cut skin or get injury; but in diseased conditions, they form clot, and induce vessel occlusion. The clotted vessel is the cause of some life-threating diseases, such as ischemic stroke or heart attack. Dr. Li is studying how this enzyme affects activation of platelet surface receptors, and thus induces clot formation, which is also called thrombosis. Project #2 is to study role of TYMP on development of atherosclerosis. Atherosclerosis is induced by deposition of lipid (fat) in the vessel wall, which leads to formation of a buildup called atherosclerotic plaque. The plaque can narrow vessel lumen and thus reduce blood volume pass through the diseased position. Severe obstruction or rupture of the plaque also can lead to clot formation, and thus stroke and heart attack. By using genetic modified mice, which are easy to have the atherosclerotic plaque in their vessel wall, Dr. Li is studying whether deletion of TYMP in mice can prevent the atherosclerotic plaque formation. Description of student training: The AHA summer student joined Dr. Li s laboratory will be assigned a mentor, a Research Assistant Professor in the lab, to perform a mentored, but independent scientific project. She/He will be guided to a considerable extent and focus, so she/he can understand the biological concepts and grasp the complexity of the project that she/he is involved. She/He will be taught the research techniques and skills that are necessary for the project. This will be either western blot or immunohistochemical staining, or both. She/He also will be trained for equipment usage, software usage, data collection and analysis, data interpretation etc. She/He will also be taught to access sources of the scientific information, such as using Pubmed, Scopus etc. She/He will be guided to prepare a 15 to 20 minutes oral presentation to summarize the work and data harvested in the lab, and give a presentation in the lab meeting of her/his last week in the lab.

3 Nalini Santanam, PhD, MPH, FAHA Professor Department of Cardiology (Medicine) Cardiovascular Disease Research Cluster Coordinator, Joan C Edwards School of Medicine at Marshall University rd Ave, 435S BBSC Huntington, WV Tel: (304) santanam@marshall.edu My laboratory is interested in studying how diet and/or exercise reduces cardiovascular disease and obesity. The following projects are available in my laboratory: Project 1: Gut microbes control behavior and appetite: The microbes that live within the gut play an important role in metabolism. These microbes can release factors that affect the brain s ability to control appetite. By modulating the appetite, gut microbes can also alter behavior (such as obesity associated stress and depression). In our laboratory we are studying changes in gut microbiome after exercise or dietary modifications and its effect on behavior and the ability of the brain to control appetite. The student will measure behavior changes in mice before and after exercise and correlate it to changes in appetite and gut microbiome. Project 2: Obesity associated stroke severity: More than 37% of Americans are obese. Obesity increase risk to ischemic strokes. We have an ongoing collaborative study to assess the effect of obesity on post-stroke recovery. The student will use serum samples from stroke patients (lean and obese) or stroked animals (lean and obese) and measure markers of inflammation and effects on vascular function.

4 Joseph Shapiro, MD Dean, Joan C Edwards School of Medicine One John Marshall Dr Huntington, WV Project 1: The Role of Oxidative Signaling through Na/K-ATPase in Salt-Sensitive Hypertension (Shapiro/ Liu) Excessive dietary salt intake is a major life-style risk factor of hypertension and related diseases such as cardiovascular and renal morbidities. Maladaptation of renal sodium handling to high salt intake is critical in development and maintenance of saltsensitive and volume-expansive hypertension. The student intern will learn to perform Oxyblots to determine protein carbonylation (a marker of oxidative stress) in tissues (kidney, heart) in wildtype and heme oxygenase-1 overexpressing mice. The student will work with a PhD student or a post-doctoral fellow to measure blood pressure changes in the mice models. He/she will also use Western blotting to determine Na/K- ATPase and other signaling molecules in the tissues from the mice models. Project 2: HO-1-SIRT1 axis attenuates NAFLD (Shaprio/Sodhi) The second project is to uncover the metabolic effects of diet induced oxidative stress and describe the molecular mechanisms involved non-alcoholic fatty liver disease (NAFLD). Prevalence of non-alcoholic steatohepatitis (NASH) is on the rise with up to 20% of the US population either having the disease or being deemed at risk. In fact, NASH-related cirrhosis is projected to be the leading indication for liver transplantation in two decades. Low levels of antioxidants and increases in oxidative stress precipitate NASH. One way to prevent this phenomenon may be by increasing the expression of heme-oxygenase 1 (HO-1), an enzyme that lowers oxidative stress. Sirtuin1 (SIRT1) is modulated by cellular redox. The student intern will measure lipid profile, and other metabolic parameters in the mice studies. He/She will use Oxyblot to determine oxidatively modified proteins and Western blot to determine changes in signaling pathways involved in the HO-1-SIRT1 axis. The student will also assist the graduate student or post-doctoral fellow in liver sectioning and staining techniques.

5 2018 AHA Summer Research Program Marshall Institute for Interdisciplinary Research (MIIR) Projects Sandrine V. Pierre, Ph.D. Associate Scientific Director Marshall Institute for Interdisciplinary Research Zijian Xie, Ph.D. Investigator and Director Marshall Institute for Interdisciplinary Research The Na/K-ATPase is the specific receptor for cardiotonic steroids (CTS) such as ouabain and digoxin. At pharmacological concentrations used in the treatment of cardiac conditions, CTS inhibit the ion-pumping function of Na/K-ATPase. At much lower concentrations, in the range of those reported for endogenous CTS in the blood, they stimulate hypertrophic growth of cultured cardiac myocytes through initiation of a Na/K- ATPase-mediated and reactive oxygen species (ROS)-dependent signaling. Project 1: Na + /K + -ATPase and endogenous cardiotonic steroids (CTS) in cardiac remodeling To examine a possible effect of endogenous concentrations of CTS on cardiac structure and function in vivo, the study will compare mice expressing the naturally resistant Na/K-ATPase α1 and age-matched mice genetically engineered to express a mutated Na/K-ATPase α1 with high affinity for CTS. Cardiac function will be assessed by echocardiographic analyses. Basal morphometric and histological analyses will be performed post-mortem to assess structural changes indicative of hypertrophy. Those assessments will include heart-weight-to-body-weight ratio, myocyte crossectional area and tissue fibrosis after trichrome staining. Re-expression of the fetal gene program will be assessed using qpcr. Project 2: Na + /K + -ATPase, novel plant cardiotonic steroids (CTS), and angiotensin IIinduced hypertrophy. Like GPCR ligands, different CTS could trigger different protein/protein interactions, resulting in biased signaling responses. By analogy with carvedilol, biased signaling through NKA may give a novel CTS a better therapeutic index than the only FDA-approved CTS digoxin. In support of this concept, we have observed that the CTS ouabain, digitoxigenin and somalin cause comparable levels of inhibition of NKA. However, while ouabain stimulates both endocytosis of Na/K-ATPase and protein kinases, digitoxigenin and somalin appear to activate either protein kinases or endocytosis. Accordingly, a study is proposed to test the hypothesis that structurally divergent CTS will have different effects on cardiac structure and function in a model of angiotensin-induced hypertrophy in the mouse. Angiotensin II will be delivered via minipumps. Cardiac function will be assessed by echocardiographic analyses. Basal morphometric and histological analyses will be performed post-mortem to assess structural changes indicative of hypertrophy. Those assessments will include heart-weight-to-body-weight ratio, myocyte crossectional area and tissue fibrosis after trichrome staining. Re-expression of the fetal gene program will be assessed using qpcr.

Na/K-ATPase amplification of oxidant stress; a universal but unrecognized clinical target?

Volume 2 Issue 2 Article 4 2016 Na/K-ATPase amplification of oxidant stress; a universal but unrecognized clinical target? Zijian Xie, PhD and Joseph I. Shapiro, MD DOI: http://dx.doi.org/10.18590/mjm.2016.vol2.iss2.4