Calcium-mediated paracrine signaling in beta cell cilia - Project Summary/Abstract This proposal presents a five-year research career development program to prepare the principal investigator (PI) Samantha Adamson, M.D., Ph.D., to become an independent physician-scientist in the field of diabetes research. The PI obtained PhD training in metabolic research at the University of Virginia with Dr. Norbert Leitinger and completed clinical training in Internal Medicine and Endocrinology at Washington University in St. Louis. The PI is currently an Instructor in Medicine and post-doctoral researcher in the lab of Dr. Jing Hughes at Washington University, studying the role of primary cilia in the function and crosstalk of pancreatic islet cells. Dr. Jing Hughes, Assistant Professor of Endocrinology at Washington University, will mentor the PI with Dr. David Piston, Chair of Cell Biology and Physiology, as co-mentor. Dr. Hughes is an emerging leader in islet and cilia research with R01 funding and is a Gateway Investigator of the Human Islet Research Network. Her expertise spans from immunology to adipocyte biology to islet cell biology, currently focusing on intra-islet cell communication via primary cilia. Dr. Hughes is a respected mentor of students, postdocs, and fellows both in the lab and in clinics. She serves as a perfect example of a successful physician-scientist who asks fundamental questions in cell biology that are grounded in clinical perspective. Dr. Piston has 30 years of research experience elucidating the molecular mechanisms that underlie hormone secretion from islets. He has mentored 37 undergraduate and graduate students, 20 post-docs, and 3 K-award fellows. The PI will take advantage of this mentorship, an expert advisory committee, and the rich and diverse scientific resources available at Washington University to define a new area of mechanism-based research in diabetes. Precise control of hormone secretion from islet cells is crucial for glucose homeostasis. Primary cilia mediate paracrine communication in islets by virtue of ciliary enrichment of somatostatin receptor 3 to control somatostatin signaling to beta cells. Preliminary data show the protein TULP3 is responsible for trafficking of somatostatin receptor to cilia and that the calcium channel polycystin 2 is required for proper calcium signaling in beta cells, an important second messenger. The research goal of this proposal is to define the mechanisms of ciliary somatostatin-mediated paracrine signaling through three focused aims. To accomplish these goals, the PI will define the role of TULP3 in trafficking of somatostatin receptor to beta cell cilia by deleting TULP3 in islets and assessing ciliary receptor localization, intracellular calcium signaling and insulin secretion in response to somatostatin compared to control islets. Further studies will focus on understanding the contributions of calcium signaling occurring in the cilia versus the cell cytosol in response to somatostatin and the role of the ciliary calcium channel polycystin. These studies will provide new insights in the pathogenesis of beta cell failure and potentially lead to the development of cilia-targeted therapy to potentiate insulin secretion for individuals living with diabetes.
