BBS Faculty Member - Rohit Kulkarni

Rohit 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
Lab Members: 9 postdoctoral fellows, 1 instructor, 1 graduate student, 4 research assistants



STUDYING GROWTH FACTOR (INSULIN/IFG-I) SIGNALLING MECHANISMS IN THE REGULATION OF INSLET CELL BIOLOGY.

My lab continues its focus on investigating the growth factor (e.g. insulin and IGF-I) signaling pathways in the modulation of glucose sensing of beta cells, proinsulin processing, 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 knockout of multiple proteins in the signaling pathways 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. A major effort is being directed towards evaluating the specificity of insulin versus IGF-I signaling and their substrates in islet 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 (MODY patients) 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 targets for 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.

To investigate the high incidence of type 2 diabetes in obese individuals we propose a potential link between adipocytederived factors (e.g. 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), and PPARgamma in islets.



Last Update: 8/22/2013



Publications

For a complete listing of publications click here.

 


 

Halperin F, Lopez X, Manning R, Kahn CR, Kulkarni RN, Goldfine AB. Insulin augmentation of glucose stimulated insulin secretion is impaired in insulin resistant humans. Diabetes 61(2):301-309, 2012.

Kim W, Lao Q, Shin Y-K, Carlson OD, Lee EK, Gorospe M,
Kulkarni RN, Egan JM. Cannabinoids induce pancreatic beta-cell death by directly inhibiting insulin receptor activation. Sci Signaling 20:5(216):ra23, 2012

Lee EK, Kim W, Tominaga K, Martindale JL, Yang X, Subaran SS, Carlson OD,
Kulkarni RN, Akamatsu W, Okano H, Egan JM, Gorospe M. RNA-binding protein HuD controls insulin translation. Mol Cell 45(6):826-835, 2012.

Kulkarni RN, Bernal-Mizrachi E, Garcia-Ocana A, Stewart AF. Perspective: Human beta-cell proliferation and intracellular signaling: driving in the dark without a roadmap. Diabetes 61: September 2012 (in press)

Morioka T, Dishinger JF, Reid KR, Liew CW, Zhang T, Inaba M, Kennedy RT,
Kulkarni RN. Enhanced GLP-1 and sulphonylurea-induced insulin secretion in islets lacking leptin signaling. Mol Endocrinol 26(6):967-976, 2012.

Welters HJ, ElOuaamari A, Kawamori D, Meyer J, Hu J, Smith DM,
Kulkarni RN. Rosiglitazone promotes PPARgamma dependent and independent changes in gene expression in mouse islets. Endocrinol July 17, 2012



© 2013 by the President and Fellows of Harvard College