Shanthi Srinivasan, MD

Associate Professor of Medicine

Department of Medicine

Phone: 404-727-5298

Fax: 404-727-5767

Email: ssrini2@emory.edu

Biography

I completed my medical training at Wayne State University, School of Medicine, Detroit, Michigan and went on to do my residency and gastroenterology fellowship at the University of Michigan Hospital, Ann Arbor, Michigan. I continued my gastroenterology fellowship at Washington University, St. Louis. Following this I was on the Faculty at Wash U, St. Louis for 2 years prior to joining Emory University in 2003. My research training at the University of Michigan and at Washington University focused on neurobiology and diabetes. My clinical interest is in gastrointestinal motility disorders with a focus on diabetes and how it affects gastrointestinal motility. I am involved in teaching Medical students (Yr 2) and graduate student in the Neuroscience program.

My laboratory focuses on the factors affecting the survival and differentiation of the Enteric Nervous System (ENS). The ENS is an integrated network of neurons and glia within the wall of the gut that consists of the myenteric and submucosal plexus. Studies in my laboratory are performed in primary culture system of isolated rat embryonic enteric neuronal cells. During normal development, signaling through the Ret transmembrane tyrosine kinase is essential for the survival, proliferation and the extension of neuronal processes. Glial Derived Neurotrophic factor (GDNF) is a growth factor that acts through Ret. We have cultured enteric neurons in the presence and absence of GDNF and performed a microarray analysis to determine the genes up regulated and down regulated by GDNF. These experiments have given us clues to the new genes that are involved in GDNF mediated enteric neuronal survival and proliferation. We plan to pursue the mechanism of each of these genes on enteric neuronal survival and proliferation. Using the growth factor, Glial Derived Neurotrophic Factor (GDNF), I study the genes that are upregulated and downregulated in response to GDNF, in primary cultured enteric neurons. I also study the effects of diabetes on enteric neurons in culture and in vivo using animal models of diabetes such as the streptozotocin-model of diabetes. More recent projects in the laboratory focus on the role of the enteric nervous system in inflammatory bowel disease. We also have some new findings on the enteric nervous system influencing islet beta cell survival.

The other main focus of my laboratory is how diabetes affects the enteric nervous system and thereby altering gastrointestinal motility. Injury to enteric neurons in the setting of diabetes may include neuronal cell death as well as injury to axonal processes. The mechanisms by which diabetes causes neuronal injury are, however, poorly understood. The effects of diabetes on the ENS are examined in vivo using streptozotocin-induced diabetic rats and in vitro using primary cultures of enteric neurons. In animal models of diabetes such as the streptozotocin-induced diabetic rat we have evidence for enteric neuronal degeneration in diabetic rats. We plan to examine the mechanism of enteric neuronal apoptosis in diabetic rats, using tools such as confocal microscopy and laser capture microscopy. To correlate the changes seen in animal models of diabetes we will examine the effects of glucose on primary culture of enteric neurons. Our studies demonstrate that elevated glucose levels also cause increased apoptosis of enteric neurons in culture. We plan to dissect out the molecular mechanisms by which elevated glucose levels injure enteric neurons. Identifying the mechanism of changes in the enteric nervous system seen in diabetes can help us develop new targets for the treatment of the gastrointestinal motility disorders seen in this disease.

My clinical interest is in gastrointestinal motility disorders with a focus on diabetes and how it affects gastrointestinal motility. Currently my clinical responsibilities are at the Veterans hospital where I the Chief of the GI unit.

I am involved in teaching gastrointestinal pathophysiology to medical students (Yr 2 and 3). I teach gastrointestinal motility related disorder to internal medicine residents and gastroenterology fellows. I teach graduate students in the Neuroscience program about the enteric nervous system.

Publications

S. Srinivasan, Mallappa Anitha, Simon Mwangi and Robert O. Heuckeroth. 2005 Enteric Neuroblasts Require the Phosphatidylinositol 3-kinase/Akt/Forkhead Pathway for GDNF Stimulated Survival. Molecular and Cellular Neuroscience, 29, 107-119
Xiaokun Ding, Neeraj K. Saxena1, Songbai Lin, Amin Xu, S. Srinivasan and Frank A. Anania. 2005. The role of leptin and adiponectin: a novel paradigm in adipocytokine regulation of liver fibrosis and stellate cell biology American Journal of Pathology, 2005;166(6):1655-69

Anitha Mallappa, Ghonda C, Sutliff R, Parsadanian A, Mwangi S, Sitaraman S and S. Srinivasan. GDNF rescues hyperglycemia-induced diabetic enteric neuropathy through activation of the PI-3-Kinase/Akt pathway. Journal of Clinical Investigation, 2006; 116 (2): 344-356. Associated editorial: Christopher K. Rayner and Michael Horowitz Gastrointestinal motility and glycemic control in diabetes: the chicken and the egg revisited? J. Clin. Invest. 2006 116: 299-302.

Anitha M, B Chandrasekharan, Salgado J, Grouzmann E, Mwangi S, Sitaraman S, Srinivasan, S. GDNF modulates enteric neuronal survival and proliferation through Neuropeptide Y- Gastroenterology, in press, June 2006,
DOI: 10.1053/j.gastro.2006.07.019

Simon Mwangi, Mallappa Anitha, Haian Fu, S. Srinivasan. GDNF-mediated enteric neuronal survival involves GSK-3ÿ phosphorylation and coupling with 14- 3-3 Neuroscience (2006), doi:10.1016/j.neuroscience.2006.07.050