Rohit N. Kulkarni, M.D., Ph.D.
1. EXPLORING GROWTH FACTOR (INSULIN/IGF-I) SIGNALLING MECHANISMS IN THE REGULATION OF ISLET CELL BIOLOGY.
It is well established from studies over the last decade, including our own, that insulin and IGF-I signaling play critical roles in the modulation of glucose sensing of beta cells, mitochondrial function, protection against apoptosis and in regulating the expression of transcription factors in islet cells. We have created multiple genetic models to examine the roles of insulin and IGF-1 receptors and their substrates (insulin receptor substrates; IRS-1,2,3,4) in islet biology. For example, we have used the Cre-LoxP technique to create beta- and alpha-cell-specific insulin receptor and IGF-1 receptor knockouts to complement in vitro models using primary islets from humans and rodents and derived beta and alpha cell lines from the knockouts. Using these powerful and unique reagents we are currently dissecting the cross-talk between insulin, IGF-I, glucose, and incretin (glucagon like-peptide-1) signaling pathways in islet cells. These studies have provided novel insights into mechanisms that regulate beta cell death and provide clues to insulin/IGF-I-independent pathways that are involved in hormone secretion, synthesis, cell proliferation and autocrine/paracrine interactions between islet cells.
A major effort is being directed towards evaluating the specificity of insulin versus IGF-I signaling and their substrates in beta cell growth and apoptosis (including endoplasmic reticulum (ER) stress) during embryonic and adult life. We are using transplantation and parabiotic approaches and techniques that allow us to investigate inter-organ communication (e.g. between islets and liver; islets and brain; islets and adipose) to complement the in vivo and in vitro studies described above. Finally, we are studying the pathways utilized by lymphocytes that allow regeneration of beta cells in type 1 diabetes using NOD mice. These studies will provide critical information on several fronts - first, it will allow us to gain greater insights into the fundamental physiological mechanisms that govern the normal growth and functioning of pancreatic islets; second, it will provide a physiological basis to identify targets in signaling pathways that would be useful to design potential therapeutic strategies to prevent beta cell death and to plan alternative approaches to generate new beta cells to prevent and/or cure type 1 and type 2 diabetes.
2. INDUCED PLURIPOTENT STEM CELLS AS A POTENTIAL SOURCE OF REGENERATION.
There continues to be considerable debate regarding the origin of human and rodent islet cells. A major focus in our laboratory is to derive induced pluripotent stem (iPS) cells from skin fibroblasts and/or blood cells derived from living human donors and rodent models with the long term goal of differentiating them into mature islet cells (e.g. insulin and glucagon secreting cells). There is also a focus on differentiating iPS cells into mature cells that are involved in common complications observed in patients with type 1 and type 2 diabetes (e.g. vascular endothelial cells, kidney cells, retinal pericytes). These approaches allow us to generate unique cells that maintain the genetic make up of the living individual that would otherwise be unavailable, with the potential for characterizing their signaling properties, testing drugs in vitro and the possibility of transplantation in suitable patients.
3. LINKING TYPE-2 DIABETES AND OBESITY AT THE LEVEL OF THE ISLET.
While the high incidence of type 2 diabetes in obese individuals is well documented, the mechanisms that promote islet dysfunction in these individuals are not fully understood. We propose a potential link between leptin and growth factor signaling pathways and their cross-talk with glucose signaling, at the level of the islet, to underlie important mechanisms that regulate islet function and growth. This hypothesis is being examined using islet-cell-specific knockouts of insulin and/or IGF-1 receptors and their substrates and the leptin receptor (ObRb) in mice. A second approach is focused on studying pathways that link leptin/insulin signaling with individual pathways that utilize the tribbles protein (TRB3), PPARgamma, and PGC1alpha in islets, all of which are important in other metabolic tissues such as the liver.
Dr. Kulkarni is a Principle Investigator at the Joslin Diabetes Center, Associate Professor of Medicine and a Faculty Member of the BBS Graduate Program at Harvard Medical School and Director of the Specialized Assay Core. Dr Kulkarni graduated with MD and PhD degrees from St. John's Medical College and the Royal Postgraduate Medical School, University of London, England. While pursuing his doctoral thesis on regulatory peptides modulating islet function in Prof. Steve Bloom's laboratory in England, Dr Kulkarni trained in the Diabetes Unit at Hammersmith Hospital in London.
He moved to Boston, obtained the F32 National Research Scholarship Award (NIH), and completed a Post-Doctoral Fellowship in the laboratory of Prof. C. Ronald Kahn. Subsequently, he received the K08 Clinician Scientist Development Award (NIH) and Best Presentation Award by a K08 Awardee; he is the recipient of the Endocrine Society Ernst Oppenheimer Laureate Award for Outstanding Work by a Young Investigator, elected to the American Society for Clinical Investigation, and recipient of the Endocrine Society Visiting Professorship in Endogenous Pancreas Preservation. Dr. Kulkarni has been on the Joslin Staff and Harvard Medical School Faculty since 1999, and currently serves on the Editorial Boards of Journal of Clinical Investigation, Endocrinology, and J of Endocrinology.