ACCORD

Administrative Core

Sundaram
Umapathy Sundaram, MD
Chairman
Phone: (304) 691-1841
sundaramu@marshall.edu

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My training and career to date has ideally positioned me to serve as the Principal Investigator and Program Director of the Center of Biomedical Research Excellence (COBRE) ACCORD. I have demonstrated a commitment to basic, clinical and translational research since my undergraduate training in Bioengineering at Johns Hopkins University during which my research at the National Institutes on Aging led to multiple co-authored publications in blood brain barrier drug entry and distribution modeling. Since graduating from the Medical College of Ohio, completing my residency in internal medicine at the University of Michigan and gastroenterology subspecialty training at Yale University, I have been actively involved in patient care, teaching and research funded by NIH, AGA, AHA, and CCFA. Over the years investigator initiated and multi center prospective clinical studies have been in Hepatitis C, inflammatory bowel disease, peptic ulcer disease and Barrett’s esophagus. The basic and translational research has been funded by NIH RO1s and currently an NIH RO1 (DK 67420) to study regulation of glucose and Na homeostasis as it pertain to diseases such as obesity and hypertension. Most recently, I was the Principal Investigator of the newly funded NIGMS IDeA Clinical Translational Research (CTR) U54 grant (1 U54 RR033567-01) at the West Virginia Clinical and Translational Science Institute (WVCTSI).

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Internal Advisory Committee

An Internal Advisory Committee (IAC) has been established with senior leaders from MU JCESOM having the necessary expertise and experience in the success of the ACCORD and the COBRE. In addition to support and oversight of the progress of the COBRE, the IAC holds quarterly progress meetings, reviews pilot grant proposals, and provides programmatic recommendations to the COBRE PD/PI. The IAC is also integral to the Evaluation Plan proposed for this COBRE. Emphasizing the importance of this COBRE for the Marshall University, the Provost, Dr. Avinandan Mukherjee chairs the IAC, which consists of the following individuals:


Dr. Avinandan Mukherjee
Provost and Senior Vice President for Academic Affairs 
mukherjeea@marshall.edu

Previously, As the Dean of the AACB-accredited Lewis College of Business at Marshall University, Dr. Mukherjee secured the largest gift in college history of $25 million from Brad and Alys Smith and garnered more than $750,000 in research and community grants. Under his leadership, the Lewis College of Business became nationally ranked in several media outlets. Both the Doctor of Business Administration program and the first fully online program from the Lewis College of Business were developed and launched as well as the first STEM program from the College. Dr. Mukherjee created the iCenter – Center for Entrepreneurship and Innovation and promoted numerous experiential learning initiatives including the Business and Economics Research Symposium. Dr. Mukherjee is a tenured Professor of Marketing and a distinguished researcher, with his published research having been cited more than 5,400 times, with an H-index of 28. Dr. Mukherjee has been a full-time faculty member in the United States (Marshall, Clayton State, Montclair State, Penn State), United Kingdom (Bradford), Singapore (NTU), and India (IIM). He has been a visiting faculty at Rutgers Business School, NJIT, INSEAD, Copenhagen Business School, ESC Toulouse, and Kathmandu University, among others. Additionally, Dr. Mukherjee has directed executive development programs and consulted with companies in the USA, UK, Denmark, India, China, Bangladesh, Singapore, and Malaysia.

Davies
John Maher, PhD
Vice President for Research
maherj@marshall.edu

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The COBRE proposal requires scientific and managerial leadership at the institutional, state and inter-institutional level to develop the collaborative and participative atmosphere necessary for effective performance. I have a broad background in scientific leadership and management of cross-functional programs that will facilitate Marshall’s successful growth through the project and the successful achievement of multi-institutional project objectives. My expertise in strategic planning and management of large, complex projects will be applied at the steering team level to assure that the organizational foundation of the project components is properly designed and executed.

Sundaram
Monica Valentovic, PhD
Professor & Research Cluster Coordinator 
Phone: (304) 696-7332
valentov@marshall.edu

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Obesity is a serious health condition within the United States that contributes to increasing the risk of other disease. The current statistics have reported that 33% of Americans are obese. In West Virginia the incidence of obesity is over 35%. Postmenopausal women who are obese have a higher risk of developing breast cancer. It is anticipated that almost 232,000 women will be diagnosed with breast cancer in 2015 and many of these individuals will be obese. The mechanism for the increased risk of cancer in obesity is not known and probably is mediated through a complex interaction of various factors. New treatment modalities are needed to address reducing the development of breast cancer.

Sundaram
Umapathy Sundaram, MD
Vice Dean of Research
Phone: (304) 691-1841
sundaramu@marshall.edu

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My training and career to date has ideally positioned me to serve as the Principal Investigator and Program Director of the Center of Biomedical Research Excellence (COBRE) ACCORD. I have demonstrated a commitment to basic, clinical and translational research since my undergraduate training in Bioengineering at Johns Hopkins University during which my research at the National Institutes on Aging led to multiple co-authored publications in blood brain barrier drug entry and distribution modeling. Since graduating from the Medical College of Ohio, completing my residency in internal medicine at the University of Michigan and gastroenterology subspecialty training at Yale University, I have been actively involved in patient care, teaching and research funded by NIH, AGA, AHA, and CCFA. Over the years investigator initiated and multi center prospective clinical studies have been in Hepatitis C, inflammatory bowel disease, peptic ulcer disease and Barrett’s esophagus. The basic and translational research has been funded by NIH RO1s and currently an NIH RO1 (DK 67420) to study regulation of glucose and Na homeostasis as it pertain to diseases such as obesity and hypertension. Most recently, I was the Principal Investigator of the newly funded NIGMS IDeA Clinical Translational Research (CTR) U54 grant (1 U54 RR033567-01) at the West Virginia Clinical and Translational Science Institute (WVCTSI).

Mentoring Committee

Receipt of this COBRE grant will allow the individual junior investigators the unique opportunity for not only substantial financial support but also focused mentoring opportunities to aid them with the move to independence. Many IDeA institutions lack the senior funded faculty “bench strength.” While we have been actively growing this critical mass over the last few years at MU JCESOM, it behooves us to realize, mentoring requires a “village” having a deliberate infrastructure, not just individual mentors. Therefore, we had established a Mentoring Committee (MC) more than a year ago which includes not only individual project mentors, but also senior investigators from across the MU JCESOM with an equally impressive track record of investigation and mentorship. The junior investigators and mentors have been meeting regularly for more than a year to not only conduct review of research projects and grant proposals, but also to discuss career trajectories and pathways, promotion and tenure, time, fiscal and lab management, and networking. The MC is chaired by Dr. Elaine Hardman. In this capacity she will coordinate mentoring for this COBRE proposal. She has had an active and well-funded research laboratory for more than 20 years. As a Senior Faculty member in Biomedical Sciences, she has mentored newer faculty members including Drs. Piyali Dasgupta, Maria Serrat and Travis Salisbury. Drs. Dasgupta and Serrat have obtained NIH R15 funding and all are making good progress toward independence. Participation in ACCORD COBRE will greatly enhance this progress. Along with the MC, Dr. Hardman will coordinate mentoring activities to insure that mentors and junior investigators are meeting regularly and that junior investigators are receiving the expected guidance. She will review mentors’ quarterly reports prior to the IAC and EAC meetings and prepare a summary for these committees. She will review attendance at seminars, meetings with visiting professors and meeting presentations to ensure that junior investigators are meeting these obligations as outlined in their quarterly plans. The Mentoring Committee members are (in addition to individual project mentors in table below):


Richard Egleton, PhD
Assistant Dean, Biomedical Sciences Graduate Program 
Phone: (304) 696-3523
egleton@marshall.edu

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I have two main roles in the CoBRE application. My primary role as co-director of the Biomedical Sciences program is to help mentor the COBRE mentees in graduate education. This includes guiding the CoBRE mentees through the various rules and regulations that govern graduate education, as well as being a resource for helping them develop mentoring plans and mentoring contracts with both undergraduate and graduate students that work in their laboratories. My secondary role in the grant is as another researcher with transport experience. My research over the last 20 years has focused on several aspects of transport and drug delivery during disease. This includes investigating the regulation of both transcellular transport and paracellular transport routes. Though these studies have largely been looking at the blood brain barrier, many of the core concepts (regulated ion transport, tight junctions) are common to other barrier tissues like the gut and kidney.

Gress
Todd Gress, MD, MPH
MCRC Medical Director
gress@marshall.edu

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I have the expertise, leadership, training, and motivation necessary to successfully support the Biostatistics and Study Design Resource proposed in this COBRE titled Appalachian Center for Cellular transport in Obesity Related Disorders (ACCORD). I have a strong background in Biostatistics and Epidemiology. I have been teaching Biostatistics and Epidemiology for over 15 years. During this time, I have assisted numerous students, residents, and faculty with their research projects. This effort has led to numerous abstracts, regional and national presentations, and publications. We have formalized this process of assisting trainees and faculty in research through development of the Biostatistics and Study Design Clinic in the Department of Clinical and Translational Sciences (DCTS). I also serve as the medical director for clinical trials, overseeing all clinical trials activity for the school of medicine, including investigator-initiated clinical trials. I am actively involved in all of the pilot award efforts in the school of medicine, having served in the roles of leader, reviewer, and pilot award selection committee member

Ruth Keri, PhD
Case Western Reserve University School of Medicine
Professor
Phone: 216-368-3495
keri@case.edu

For more than 17 years, my research has focused on the genomic and signaling mechanisms that control mammary gland development and cancer. As reflected by my position as a member of the steering committee for the Gene Expression and Genotyping Core Facility at CWRU, I have significant expertise in the acquisition and use of gene expression profiling data to identify novel factors that may control the phenotypes of breast cancer cells.  This has involved generating and using data from cell lines and genetically manipulated mouse models of breast cancer as well as evaluation of publicly available human breast cancer array data. I have designed and used mouse models of disease throughout my research career, including assessing the efficacy of therapeutic agents such as vitamin D analogs, rapamycin, and dasatinib in mammary cancer models. I also have significant experience assessing drug synergy, in vitro and in vivo. 

Philip Kern, MD
University of Kentucky
Director of the Center for Clinical and Translational Science
Phone: 859-323-2232

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I am the director of the University of Kentucky (UK) Center for Clinical and Translational Science (CCTS) and Associate Provost for Clinical and Translational Science, where I report directly to the Provost and to the University Vice President for Research. The CCTS is a University of Kentucky (UK) campus-wide Center that houses the institutional Clinical and Translational Science Award (CTSA); it is supported by the CTSA grants (UL1/KL2/TL1) and institutional funds with a total yearly budget over $10 million. The mission of the CCTS is to stimulate innovative translational science on campus, promote development of the translational workforce, stimulate team science, in part through a robust pilot grant program, work with the healthcare system to develop efficiencies and improved strategies for translational research, build a clinical trials network and generally serve as a nexus at UK and in the Central Appalachian region for research that improves health in the community. That core focus on rural communities and their health needs and challenges is one of numerous vital links between the CCTS and the University of Kentucky Center for Appalachian Research in Health Sciences (UK-CARES). I have been a strong supporter of UK-CARES initiatives since the center’s inception in 2017 and in particular, am committed to continuing to serve on the Institutional Advisory Board. My own research interests in obesity, metabolic syndrome, and diabetes align with challenges that UK-CARES addresses in the central Appalachian region of Kentucky.

I was the inaugural Director of UK’s Barnstable Brown Diabetes and Obesity Center, founded in 2009, and have a long history of studying adipose and muscle biology and I am engaged in both basic and clinical research related to obesity, metabolic syndrome, inflammation, lipid metabolism, diabetes and insulin resistance, as outlined below. As a clinician-scientist, I have become recognized as an important collaborator and advisor on many other investigators’ grant-funded programs. In recognition of my research achievements, I am honored to have been selected by my peers and UK leadership as a 2019 University Research Professor, the premier research recognition at our institution

Davies
Jung Han Kim, PhD
Professor, Department of Pharmacology
kimj@marshall.edu

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My experience and qualifications make me well suited for serving as a mentor in the project. Over the several years, I supervised more than one hundred undergraduate and twenty graduate students. I served as a Member in twenty graduate student thesis committees and served as Advisor/Chair for six M.S. and Ph.D. students. I have mentored three postdoctoral fellows who became a successful independent scientist. With my mentees I have produced multiple peer-reviewed publications. In addition, I have a solid background in genetics, nutritional sciences and physiology, with specific training and expertise in gene mapping, positional cloning, and physiological analysis. My research includes identifying genetic factors underlying obesity and type 2 diabetes and the related pathophysiological pathways. With my research endeavors I have developed useful animal models for obesity and type 2 diabetes including TALLYHO mice that are well served in the project. As PI on several Foundation- and NIH-funded grants, I have built a strong research program and have a track record of accomplished and productive research projects. 

Sundaram
Gary O. Rankin, PhD
Professor & Chair 
Phone: (304) 696-7319
rankin@marshall.edu

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I am well qualified to serve as a mentor for junior scientists. I was Chair of the Department of Pharmacology from 1986-2005, and when my department was merged with the Department of Physiology, I was made Chair of the combined department, a position I still hold. Over the years, I have mentored numerous undergraduate (26), graduate (40) and medical students (18), postdoctoral fellows (7) and faculty members, both within and outside my department and institution. In addition, I am the principal investigator of the NIH-funded West Virginia IDeA Network of Biomedical Research Excellence (WV-INBRE). In this capacity, I oversee a state-wide network composed primarily of new investigators at primarily undergraduate institutions across West Virginia, and serve as mentor for several of them.

Sundaram
Umapathy Sundaram, MD
Vice Dean of Research
Phone: (304) 691-1841
sundaramu@marshall.edu

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My training and career to date has ideally positioned me to serve as the Principal Investigator and Program Director of the Center of Biomedical Research Excellence (COBRE) ACCORD. I have demonstrated a commitment to basic, clinical and translational research since my undergraduate training in Bioengineering at Johns Hopkins University during which my research at the National Institutes on Aging led to multiple co-authored publications in blood brain barrier drug entry and distribution modeling. Since graduating from the Medical College of Ohio, completing my residency in internal medicine at the University of Michigan and gastroenterology subspecialty training at Yale University, I have been actively involved in patient care, teaching and research funded by NIH, AGA, AHA, and CCFA. Over the years investigator initiated and multi center prospective clinical studies have been in Hepatitis C, inflammatory bowel disease, peptic ulcer disease and Barrett’s esophagus. The basic and translational research has been funded by NIH RO1s and currently an NIH RO1 (DK 67420) to study regulation of glucose and Na homeostasis as it pertain to diseases such as obesity and hypertension. Most recently, I was the Principal Investigator of the newly funded NIGMS IDeA Clinical Translational Research (CTR) U54 grant (1 U54 RR033567-01) at the West Virginia Clinical and Translational Science Institute (WVCTSI). 

Patrick Tso, PhD
University of Cincinnati College of Medicine
Professor, Mary M. Emery Chair of Pathology, Director of Cincinnati Mouse Metabolic Phenotyping Center
Phone: 513-558-2151
Patrick.tso@uc.edu

One of our research goals is to gain a better understanding of the mechanisms and factors regulating intestinal lipid absorption and the assembly and secretion of chylomicrons and very low density lipoproteins by the small intestine. The techniques we employ consist of conscious intestinal lymph fistula rats, lymph fistula mouse, intestinal epithelial cell culture, and also molecular biology. We are currently studying how bile salts are involved in the absorption of lipids. In addition, we are also studying the factors regulating the synthesis and secretion of apolipoproteins by the small intestine. The apolipoproteins we are studying are: apo AI, apo AIV, apo B, and apo CIII.

Sundaram
Monica Valentovic, PhD
Professor & Research Cluster Coordinator 
Phone: (304) 696-7332
valentov@marshall.edu

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Obesity is a serious health condition within the United States that contributes to increasing the risk of other disease. The current statistics have reported that 33% of Americans are obese. In West Virginia the incidence of obesity is over 35%. Postmenopausal women who are obese have a higher risk of developing breast cancer. It is anticipated that almost 232,000 women will be diagnosed with breast cancer in 2015 and many of these individuals will be obese. The mechanism for the increased risk of cancer in obesity is not known and probably is mediated through a complex interaction of various factors. New treatment modalities are needed to address reducing the development of breast cancer.


Nalini Santanam, PhD
Professor & Research Cluster Coordinator 
santanam@marshall.edu

View Nalini Santanam's work here. 

My laboratory is interested in studying gender differences in risk of cardiometabolic diseases. Cardiovascular disease (CVD) is the number one killer in women. Even after adjusting for known risk factors women still exhibit much higher annual mortality rates than men. Currently, there is no clear-cut understanding of the mechanisms that lead to these gender-specific differences in risk to CVD. Using animal models and human subjects’ samples, my laboratory investigates how diet and exercise interventions can prevent cardiac or vascular injury caused by abdominal and cardiac fat. We are also interested in studying how these interventions alter behavior and microbiome in a sex-specific manner.

My other research interest is studying the etiology of endometriosis and its associated pain. Endometriosis is a disease that affects 10-15% of women of child-bearing age and is the major cause for chronic pain and infertility. Using clinical samples and animal models of pain/endometriosis my laboratory is testing novel treatments for endometriosis.

Endometriosis is also a risk factor for ovarian cancer and endometrioid cancer. My laboratory studies mechanisms that lead to the transformation of endometriosis to cancer.

Brandon Henderson, PhD
Assistant Professor & Research Cluster Coordinator 
hendersonbr@marshall.edu

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I have the necessary background to be considered a junior investigator for this COBRE, which is
focused on cellular transport disorders in obesity related conditions. My research has focused on the molecular
neuropharmacology of nicotine addiction. I have spent a significant amount of time in my scientific career
discovering and designing small molecules that target nicotinic receptors as a means to improve tobacco
cessation. My postdoctoral research has focused on the neurobiology of addiction and how nicotine alters
midbrain neurons of the nigrostriatal reward pathway. My lab at Marshall University uses pharmacology,
medicinal chemistry, electrophysiology, electrochemistry, microscopy, and animal models to: 1) study how
addictive drugs modulate neurons involved in reward pathways, 2) study how these drugs alter DA release,
and 3) discover novel small molecules that may aid in cessation.

Ji Bihl, PhD
Associate Professor 
bihlj@marshall.edu

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I have the training, expertise, motivation, and leadership necessary to supervise and collaborate with the
current research project. I have a broad background in integrated basic and translational research projects,
including the studies on the role of extracellular exosomes (EXs) and microvesicles (MVs), stem cell therapy,
and the renin-angiotensin system in ischemic stroke, hemorrhagic stroke, and diabetic ischemic stroke.
Several signal pathways such as PI3K/Akt/eNOS, oxidative stress, and microRNA mechanisms are actively
investigated. My research approaches include using transgenic mouse models in combination with animal
surgeries, such as telemetric probe implantation for recording blood pressure and heart rate,
minipump/microinjection for chronic/acute drug administration, and animal modeling for MCAO-induced
ischemic stroke. I have also been actively involved in translational studies by investigating the role of
endothelial progenitor cells (EPCs) and MVs/EXs in stroke and diabetes patients. My laboratory is very well
established to perform exosomal research, especially related to microRNA delivery. As a note, my publication
history reflects my maiden name (Chen J) and I have been publishing under my married name (Bihl J) since
2014.

Executive Advisory Committee

Lisa Cassis, PhD
University of Kentucky College of Medicine
Vice President of Research
Professor of Pharmacology and Nutritional Sciences
Co-Director, Division of Nutritional Sciences
Graduate Faculty in Nutritional Sciences
Cardiovascular Research Center
MD/PhD Program Mentor
Phone: 859-323-4933
Email: lcassis@uky.edu

​

Pradeep Dudeja, PhD
University of Illinois at Chicago Department of Medicine
Professor of Physiology in Medicine Director, Scholarly Activities Division of Gastroenterology and Hepatology
Phone: 312-569-7434
Email: pkdudeja@uic.edu

Naji Abumrad, MD
Vanderbilt University Medical Center
Professor of Medicine
Phone: 615-343-2735
Email: naji.abumrad@vanderbilt.edu

Project Investigators

Project 1 - Regulation of sodium dependent bile acid absorption in obesity

Mentor: Dr. Jung Han Kim

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Subha Arthur, PhD
Assistant Professor
arthursu@marshall.edu

Dysregulation of lipid homeostasis is a key characteristic of obesity, resulting in sequelae such as diabetes, cardiovascular diseases, fatty liver diseases, etc. Assimilation of lipids is entirely dependent on bile acid availability in the intestine. Bile acids are absorbed in the terminal ileal villus cell brush border membrane (BBM) via Na-bile acid-co-transporter (ASBT) requiring a favorable transcellular Na gradient provided by basolateral membrane (BLM) Na/K-ATPase. Novel preliminary findings suggest that in multiple species (including human), ASBT is upregulated secondary to Na/K-ATPase downregulation. Thus, the hypothesis of this project is that ASBT is uniquely regulated at the level of the cotransporter in the BBM, along with Na/K-ATPase in the BLM in intestinal cells during obesity. The observations of this study will result in novel data which will enhance our understanding of bile acid absorption, thereby, lipid assimilation dysregulation during obesity, and potentially lead to more efficacious treatment modalities.

Project 3 - Coupling nutrient absorption to gut hormone secretion is altered in obesity

Mentor: Dr. Uma Sundaram

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Alip Borthakur, PhD
borthakur@marshall.edu

Obesity and its comorbidities have reached epidemic proportions worldwide. In genetically susceptible individuals, obesity results from an imbalance in the body’s regulation of energy intake, expenditure, and storage. Dietary nutrients absorbed in the proximal small intestine and assimilated in different tissues have a profound effect on overall energy homeostasis. The incretin hormones glucagon-like peptide 1 (GLP1) and glucose-dependent insulinotropic peptide (GIP) secreted postprandially by epithelial enteroendocrine cells (EECs) regulate energy balance and glucose homeostasis via stimulation of insulin secretion and regulation of appetite. Altered production and release of gut hormones by EECs play a major role in metabolic disorders such as obesity and type 2 diabetes. Further, increasing evidence suggests that the metabolic benefits of gastric bypass surgeries are partly attributable to increased production of GLP1 by EECs Therefore, it is critical to understand the mechanisms of postprandial gut hormone release in EECs and its dysregulation in obesity. Recent studies have shown that nutrient sensing and transport by the epithelial nutrient transporters (for example, Na+-glucose co-transport by SGLT1 and proton-coupled peptide transport by PepT1) into EECs critically regulate gut hormone secretion. However, the mechanisms of the role of SGLT1/PepT1 in modulating hormone secretion and their alterations in obesity are not fully understood. Therefore, we hypothesize that nutrient transport into EECs mediated by SGLT1 and PepT1 critically regulates EEC’s mechanisms to secrete incretin hormones GLP1 and GIP, which are altered in obesity. These studies will be performed complementarily in vitro in normal mouse enteroendocrine cell line STC1 and in vivo in diet-induced obese mice. Further, to make our results translationally relevant we will use in vitro human enteroendocrine cell line NCI-H716 and ex vivo human intestinal organoids generated from normal and obese subjects. The studies will be performed with the following Specific Aims: (1) Elucidate the role of SGLT1/PepT1 in nutrient-induced incretin hormone production in vitro in mouse and human EECs; (2) Determine the mechanisms of alterations of EECs, SGLT1/PepT1 and GLP1/GIP in vivo in diet-induced obese mice and ex vivo in human organoids from obese subjects. The outcome of these studies will provide novel mechanistic insights into EEC cross-talk with dietary nutrients via SGLT1 and PepT1 to modulate gut hormone secretion during obesity. The important insights into the pathophysiologic basis of dysregulated EEC SGLT1 and PepT1 will provide critical novel information and define newer avenues for designing nutrient-based treatment modalities for obesity.

Project 4 - Mechanism of regulation of Down Regulated Adenoma (DRA) in obesity associated colitis induced colon cancer

Mentor: Dr. Uma Sundaram

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Balasubramanian Palaniappan, PhD
palaniappan@marshall.edu

Obesity is an epidemic in the United States especially in Central Appalachia and West Virginia, with rates of 39.7%. Obesity is known to cause diabetes, hypertension, cardiovascular diseases, metabolic syndrome, and certain types of cancer, including colon cancer. In the United States, 40% of cancer incidence is associated with overweight and obesity. In West Virginia, the prevalence of colon cancer is 49% and the mortality rate is 18%. Many reports indicate that obesity and/or obesity-related inflammation is a key factor for the etiology of colon cancer. Likewise, inflammatory bowel disease, specifically, ulcerative colitis (UC) is also an important risk factor for the development of colon cancer, namely colitis-associated colon cancer (CAC). UC increases CAC risk up to 18-20% while Crohn’s disease of the colon contributes up to 8% after 30 years of active disease. The primary function of the mammalian colon is the absorption of electrolytes (NaCl) and water. Coupled NaCl absorption is mediated by the dual operation of Na/H exchanger (NHE3) and Cl-/HCO3- exchanger (Down Regulated in Adenoma (DRA). In colon cancer and the UC colon, DRA is inhibited. However, how DRA may be affected in obesity, obesity-associated colon cancer, obesity-associated colitis, and obesity-associated colitis-related colon cancer is not known. Given the prevalence of obesity and its ability to increase colon cancer incidence, how DRA, which is also important fin the pathogenesis of colon cancer, may be altered in these conditions is important to determine. During obesity, we have demonstrated that DRA is increased in the small intestine of obese Zucker rats, Tallyho mice, and obese humans. Recent preliminary studies showed that DRA activity and expression are decreased in the obese Zucker rat colon. In rat colitis induced by DSS, DRA activity and expression are diminished. Likewise, in rat colon cancer induced by azoxymethane, DRA is diminished. Further, in rat colitis-associated colon cancer as well, DRA’s activity and expression are decreased. Finally, since adipocyte-derived secretome (ADS) is thought to potentially mediate the effects of obesity at multiple physiological levels, its effect was determined in vitro on human colon cancer CaCo2 cells. ADS from obese but not lean Zucker rats inhibited DRA in vitro as well. All of these novel data indicate that DRA is inhibited in multiple related conditions all of which predispose to colon cancer. Thus, the proposed study hypothesizes that colitis in obesity may especially predispose to colon cancer via inhibition of DRA. The outcome of the proposed studies will provide novel information regarding the mechanism of regulation of chloride bicarbonate exchange activity during obesity and its associated colon cancer, colitis, and CAC. This will enhance our understanding of the downregulation of DRA and malabsorption of Cl, which may play a critical role in the pathogenesis of genetic obesity, and obesity facilitated the development of colon cancer, colitis, and CAC, which could define more efficacious treatment options for obesity-associated colon cancer

Project 5 - Adipose derived secretome (ADS) uniquely regulates intestinal epithelial cell nutrient absorption during obesity

Mentor: Dr. Uma Sundaram

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Soudamani Singh, PhD
singhs@marshall.edu

Obesity commonly results from an excess accumulation of adipose tissue when caloric consumption exceeds energy expenditure. During obesity, adipose-derived secretome (ADS) has been shown to influence many physiological processes, but the effects of ADS on intestinal epithelial nutrient transport processes are not known. Our preliminary studies showed that in obese Zucker rats (OZR) the nutrient transporters Na-glucose co-transporter 1 (SGLT1; SLC5A1) and Na-dependent glutamine co-transporter 1 (B0AT1; SLC6A19) are stimulated in intestinal epithelial villus cells compared to lean Zucker rats (LZR). These effects were also observed in vitro in rat intestinal epithelial IEC-18 cells showing stimulation of SGLT1 and B0AT1-mediated uptake of glucose and glutamine, respectively, by ADS from OZR, but not LZR. Thus, SGLT1 and B0AT1 are uniquely stimulated in villus cells during obesity and ADS appears to mediate this stimulation of glucose and glutamine assimilation via distinct mechanisms. These novel observations led to the hypothesis of this proposal – ADS mediates the unique alterations in SGLT1 and B0AT1 during obesity. The overall aim of this study is to elucidate the mechanisms underlying this unique regulation of SGLT1 and B0AT1 by ADS in obesity. The outcome of this study will undoubtedly enhance our understanding of the altered absorption of the primary nutrients into the enterocytes during obesity. Further, critical data obtained from this study could pave the way for novel, more efficacious and specific nutrition-based therapies for obesity.

Completed - Inhibition of Leucine-Stimulated Induction of mTOR1 to Suppress Breast Cancer in Obesity

Mentor: Dr. Uma Sundaram

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Travis Salisbury, PhD
salisburyt@marshall.edu

Obesity is a risk factor for breast cancer, a disease that was diagnosed in nearly 3 million women in this country in 2015. Based on preliminary data, it is hypothesized that altered levels of adiponectin, leptin, and estrogen hormones found in obesity interact to activate the L-Type Amino Acid Transporter 1 (LAT1) gene. The LAT1 gene encodes an amino acid transporter that specifically promotes the uptake of neutral amino acids, including leucine. High intracellular levels of leucine are required for the activation of Mechanistic Target of Rapamycin (mTOR), a kinase that is critical to tumor growth. It is proposed that leucine-mediated increases in mTOR activity in breast cancer cells in obese women, compared with lean women lead to larger, more aggressive breast tumors that are more resistant to cancer therapy. It is anticipated that findings of this proposal will significantly enhance our understanding of obesity associated breast cancer and will potentially lead to new and more efficacious therapeutic options.

Completed Project - Dysregulated Growth Factor Transport and Accelerated Bone Elongation in Childhood Obesity

Mentor: Dr. Harmut Malluche

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Maria Serrat, Ph.D.
Assistant Professor
serrat@marshall.edu


Appalachia (WV) leads the nation in childhood obesity with about 1 in 3 children already overweight or obese. Obese children have higher rates of linear growth, accelerated skeletal maturation, and diminished bone quality. These factors can contribute to painful and debilitating conditions such as limb bowing, joint instability, fractures, and slipped capital femoral epiphyses. Insulin-like growth factor (IGF)-I, is one of two essential hormones (Growth Hormone is the other) needed for proper bone growth and is altered in obesity. Novel preliminary data demonstrate that IGF binding proteins (IGFBPs) may regulate bone elongation by entrapping IGF-I and limiting its transport into the growth plate; however, IGFBPs levels are diminished in obesity. Thus, the overall hypothesis is that a decrease in local IGF binding proteins promotes bone lengthening by allowing more IGF-I transport into growth plates. Better understanding of how the perichondrium IGF binding proteins regulate IGF-I transport into growth plates will potentially result in IGFBP based therapies to modulate the rate of bone elongation in obesity, and thus minimize the associated obesity-related morbidities of childhood.
Pilot Investigators

Pilot 1 - Characterization of the impact of high-fat diets and nicotine exposure on the gut-brain-axis: Implications toward metabolic syndromes, obesity, and addition

Mentor: Dr. Uma Sundaram

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Brandon Henderson, Ph.D.
Assistant Professor

hendersonbr@marshall.edu

West Virginia ranks number one for obesity and number two for smoking prevalence among all states. Of the 37.7% of West Virginians classified as obese, many make up the 27.4% of those that smoke in our state. While many studies have examined obesity and smoking separately, none have undertaken a detailed investigation into the connection. Early exposure to nicotine contributes to an increased risk for obesity later in life. While key indicators have been identified (increased adiposity, food intake, increased circulating insulin, and increased lipogenesis), the precise mechanism for this is yet to be determined. While there are obesity-mediated alterations in Na/K-ATPase activity in intestinal epithelial cells, nicotine has also been shown to alter the function of intestinal Na/K-ATPase. Therefore, nicotine may potentiate the obesity-mediated alterations in Na/K-ATPase activity and enhance the propensity for a metabolic syndrome that contributes to obesity. Furthermore, high-fat diets (HFDs) trigger changes in midbrain dopamine signaling that contributes addiction-related behavior, including nicotine reward and reinforcement. Thus, it is likely that while nicotine contributes to metabolic syndromes, HFDs exacerbate nicotine dependence and this results in a potentiated effect on both addiction-related brain circuitry and intestinal physiology that both contribute to metabolic syndromes and obesity.

Our primary hypothesis is that mice exposed to HFDs and nicotine will display changes intestinal physiology that contribute to metabolic syndromes and obesity. Our secondary hypothesis is that mice exposed to HFDs and nicotine will also exhibit enhanced dopamine neuron physiology compared to control or nicotine-only treated mice. These hypotheses are based on prior research that indicate nicotine contributes to metabolic syndromes and HFDs alter dopamine neurons to facilitate addiction-related behavior. We will test these hypotheses with three aims: first we will examine the impact of HFD and nicotine exposure on Na-dependent glucose uptake, GLT transport, and glutamate transport in intestinal ileal villus cells. Second, we will prepare brain slices from mice to examine changes in nucleus accumbens core dopamine release and midbrain dopamine neuron firing. Third, and finally, we will correlate the observed changes in dopamine neuron function (aim two) to changes in intestinal function to identify key mechanistic connections within the microbiome-gut-brain axis. This will highlight key future directions that will be the foundation for extramural funding along the intersection of obesity and addiction. One key benefit for this work is that while brain and intestinal tissue are harvested, other tissue (liver, kidney, colon, adipose) can be preserved for follow-up assays that will be highlighted throughout the course of the proposed research.

Completed Pilot - Unique Regulation of Glucose and NaCl absorption in diet-induced obesity

Mentor: Dr. Uma Sundaram

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Balasubramanian Palaniappan, Ph.D.
Assistant Professor
palaniappan@marshall.edu


In obesity, diabetes and hypertension most commonly coexist and cause deregulation of glucose absorption and NaCl homeostasis in the mammalian small intestine. The overall hypothesis of the project is that glucose and NaCl absorption are uniquely regulated in the mammalian small intestinal epithelial cells during diet-induced obesity. The primary goal of this project is to determine, how diet-induced obesity, which is the predominant cause of human obesity, alters glucose, and NaCl absorption in the intestine.

To investigate the regulation of glucose absorption in diet-induced obesity, the activity and expression of the primary sodium-dependent glucose co-transporter (SGLT1) were measured in small intestinal villus cells of C57BL/6 mice fed with a high-fat diet (HFD) compared to a low-fat diet (LFD) fed mice. SGLT1 activity was significantly higher in HFD as compared to LFD fed mice. Na/K-ATPase activity, which provides the favorable transcellular Na gradient for glucose transport, was significantly decreased in HFD mice. The mechanism of SGT1 stimulation in HFD fed mice is secondary to an increased affinity (decreased Km) of the co-transporter for glucose without change of the maximal velocity (Vmax). Molecular analysis showed no difference in SGLT1 mRNA and protein expressions between LFD and HFD mice. Taken together, our data suggest that increased glucose absorption in HFD mice was secondary to an increase in the affinity of the co-transporter for glucose without altering the co-transporter numbers at the cellular and membrane levels.  

Parallel to increased Na-glucose cotransport (SGLT1 activity), Cl-/HCO3- exchange, a major component of coupled NaCl absorption in mammalian intestine, was also increased in HFD, compared to LFD mice. Mechanism of stimulation of Cl-/HCO3- exchange was secondary to an increase in the number of the exchanger (Vmax) with no alteration of the affinity (Km) of the exchanger for Cl. Further, the mRNA levels and protein expression of DRA and PAT1, the Cl-/HCO3- exchangers known to mediate NaCl absorption in the mammalian intestine, were increased in HFD mice villus cells as compared to LFD mice. Overall, our results suggested that in diet-induced obesity, SGLT1 and Cl-/HCO3- exchange are regulated via distinct mechanisms.

Future studies: Our studies on the alteration of SGLT1 and Cl-/HCO3- exchange in diet-induced obesity will be further extended by elucidating the molecular mechanisms of posttranslational regulation of SGLT1 and of the modulation of DRA/PAT1 at the level of transcription and/or via increased targeting to BBM of villus cells.    

Completed Pilot - Regulation of human intestinal nutrient transporters by adipocyte-derived factors

Mentor: Dr. Uma Sundaram

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Jennifer Haynes, Ph.D.
Assistant Professor

haynesje@marshall.edu

Obesity is a complex disease linked to several serious health conditions, including cardiovascular disease, type 2 diabetes, hypertension, and several types of cancer. Intestinal nutrient absorption is altered in obesity; however, the underlying mechanisms are not well understood. The overall hypothesis is that during obesity, adipocyte-derived factors alter nutrient transporter function in intestinal epithelial cells (IECs), which ultimately affects nutrient homeostasis throughout the body. Thus, the aim of this project is to determine the effect of adipocyte-derived factors on activity and expression of human IEC nutrient transporters and identify potential regulatory pathways involved. Patient-derived intestinal organoid-based culture models will be used to examine the uptake of key nutrients in human IECs co-cultured with primary human adipocytes. The effect of adipocyte-derived factors on expression of genes involved in nutrient transport, and related energy metabolic and signaling pathways will also be determined. These studies will provide insight into the regulation of intestinal nutrient absorption processes by adipocyte-derived factors. Identifying and understanding the molecular mechanisms underlying obesity-related alterations in nutrient absorption is key for designing future therapeutics.

Completed Pilot - Regulation of Na-glutamine co-transport by adipose-derived secretome in intestinal epithelial cells

Mentor: Dr. Uma Sundaram

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Soudamani Singh, Ph.D.
Assistant Professor
singhs@marshall.edu

In the normal mammalian small intestine, absorption of dietary glutamine, which is a primary nutrient for enterocytes, is mediated by Na-dependent glutamine co-transporter (B0AT1; SLC6A19) expressed in the brush border membrane of villus cells. Obesity usually results from a surplus accumulation of adipose tissue when caloric consumption goes beyond energy expenditure in genetically predisposed individuals. One of the critical factors governing energy homeostasis is the intestinal absorption of nutrients. However, not much is known about how intestinal absorption of nutrients may be altered in obesity. We have shown that in obese Zucker rats (OZR), a genetic model of obesity, B0AT1 is stimulated in villus cells compared to lean Zucker rats (LZR) via distinct mechanisms. B0AT1 stimulation is due to an increase in the number of co-transporter (Vmax) without any alteration in the affinity of the co-transporter for glutamine. Our results suggest that B0AT1 stimulation is mediated through the altered membrane trafficking that results in increased apical cell surface B0AT1 protein levels in obese rat intestinal villus cells. However, there is no change in the relative abundance of newly synthesized B0AT1 transcripts and/or mRNA stability.

Completed Pilot - A novel probiotics-based approach to improve enteroendocrine cell function in obesity

Mentor: Dr. Uma Sundaram

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Alip Borthakur, Ph.D.
Assistant Professor
borthakur@marshall.edu


Obesity and its comorbidities have reached epidemic proportions worldwide. In genetically susceptible individuals, obesity results from an imbalance in the body’s regulation of energy intake, expenditure, and storage. Dietary nutrients absorbed in the proximal small intestine and assimilated in different tissues have a profound effect on overall energy homeostasis. The incretin hormones glucagon-like peptide 1 (GLP1) and glucose-dependent insulinotropic peptide (GIP) secreted postprandially by epithelial enteroendocrine cells (EECs) regulate energy balance and glucose homeostasis via stimulation of insulin secretion and regulation of appetite. Altered production and release of gut hormones by EECs play a major role in metabolic disorders such as obesity and type 2 diabetes. Further, increasing evidence suggests that the metabolic benefits of gastric bypass surgeries are partly attributable to increased production of GLP1 by EECs Therefore, it is critical to understand the mechanisms of postprandial gut hormone release in EECs and its dysregulation in obesity. Recent studies have shown that nutrient sensing and transport by the epithelial nutrient transporters (for example, Na+-glucose co-transport by SGLT1 and proton-coupled peptide transport by PepT1) into EECs critically regulate gut hormone secretion. However, the mechanisms of the role of SGLT1/PepT1 in modulating hormone secretion and their alterations in obesity are not fully understood. Therefore, we hypothesize that nutrient transport into EECs mediated by SGLT1 and PepT1 critically regulates EEC’s mechanisms to secrete incretin hormones GLP1 and GIP, which are altered in obesity. These studies will be performed complementarily in vitro in normal mouse enteroendocrine cell line STC1 and in vivo in diet-induced obese mice. Further, to make our results translationally relevant we will use in vitro human enteroendocrine cell line NCI-H716 and ex vivo human intestinal organoids generated from normal and obese subjects. The studies will be performed with the following Specific Aims: (1) Elucidate the role of SGLT1/PepT1 in nutrient-induced incretin hormone production in vitro in mouse and human EECs; (2) Determine the mechanisms of alterations of EECs, SGLT1/PepT1 and GLP1/GIP in vivo in diet-induced obese mice and ex vivo in human organoids from obese subjects. The outcome of these studies will provide novel mechanistic insights into EEC cross-talk with dietary nutrients via SGLT1 and PepT1 to modulate gut hormone secretion during obesity. The important insights into the pathophysiologic basis of dysregulated EEC SGLT1 and PepT1 will provide critical novel information and define newer avenues for designing nutrient-based treatment modalities for obesity.​

COBRE Administrative Staff

Rong Fan
Business Administrator
rong.fan@marshall.edu
Phone: (304) 691-1844

Cores
Evaluation Team

Sundaram
Umapathy Sundaram, MD
Chairman
Phone: (304) 691-1841
sundaramu@marshall.edu

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My training and career to date has ideally positioned me to serve as the Principal Investigator and Program Director of the Center of Biomedical Research Excellence (COBRE) ACCORD. I have demonstrated a commitment to basic, clinical and translational research since my undergraduate training in Bioengineering at Johns Hopkins University during which my research at the National Institutes on Aging led to multiple co-authored publications in blood brain barrier drug entry and distribution modeling. Since graduating from the Medical College of Ohio, completing my residency in internal medicine at the University of Michigan and gastroenterology subspecialty training at Yale University, I have been actively involved in patient care, teaching and research funded by NIH, AGA, AHA, and CCFA. Over the years investigator initiated and multi center prospective clinical studies have been in Hepatitis C, inflammatory bowel disease, peptic ulcer disease and Barrett’s esophagus. The basic and translational research has been funded by NIH RO1s and currently an NIH RO1 (DK 67420) to study regulation of glucose and Na homeostasis as it pertain to diseases such as obesity and hypertension. Most recently, I was the Principal Investigator of the newly funded NIGMS IDeA Clinical Translational Research (CTR) U54 grant (1 U54 RR033567-01) at the West Virginia Clinical and Translational Science Institute (WVCTSI).

Davies
John Maher, PhD
Vice President for Research
maherj@marshall.edu

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The COBRE proposal requires scientific and managerial leadership at the institutional, state and inter-institutional level to develop the collaborative and participative atmosphere necessary for effective performance. I have a broad background in scientific leadership and management of cross-functional programs that will facilitate Marshall’s successful growth through the project and the successful achievement of multi-institutional project objectives. My expertise in strategic planning and management of large, complex projects will be applied at the steering team level to assure that the organizational foundation of the project components is properly designed and executed.


Donald A. Primerano, PhD
Professor; Microbiology
Section Head; and Co-Director,
Genomics and Bioinformatics Core Facility
primeran@marshall.edu

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My primary research interests are in the discovery of chronic disease susceptibility genes using next generation sequencing, expression profiling and bioinformatic approaches. I currently serve as the Co-Director of the Genomics and Bioinformatics Core Facility (GABC) and as a member of the WV-IDeA Network of Biomedical Research Excellence (WV-INBRE) Administrative Core and WV Cancer Genomics Steering Committee. I have served as the Genomics Core Director from 1999-2011. As Co-Director, I have experience in (1) developing sequencing strategies and service relationships between the GABC and research networks needing genomic analyses, (2) providing overall direction to a core with evolving technologies and institutional responsibilities, (3) assisting individual investigators in designing genomic experiments and (4) providing training in genomic technologies.