Rohit N. Kulkarni


Department of Cell Biology
Joslin Diabetes Center
One Joslin Place, Room 602
Boston, MA 02215
Tel: (617) 713-3460
Fax: (617) 713-3476
Email: rohit.kulkarni@joslin.harvard.edu
7 postdoctoral fellows, 3 research assistants

 

 

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 and cell growth. 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.

 

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.

 

References:

 

BBS webpage updated 1/28/2011