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Investigator Specifics:
Professional Details:
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CV

Member of Section:
Cellular and Molecular Physiology

Core Director:

Specialized Assay Core

Current Fellows, Students, or Lab Members:
Charlotte Hinault, PhD
Ashley Holman
Jiang Hu
Dan Kawamori, MD, PhD
Hui Li
Chong Wee Liew, PhD
Siming Liu, Ph.D.
Tomoaki Morioka, MD,PhD
Susana Silva, Ph.D.

Past Fellows, etc.:
Anke Abmann
Rebecca Anderson
Anke Assmann, M.D.
Stephanie DeJardin
Anthony Faber
Sarah Flier
Lina Garcia
Fausto Hegardt
Fausto Hegardt
Amarnath Kurpad
Susan Maya
Emily Niu
Terumasa Okada
Umut Ozcan
Irene Reske
Edward Rhee
Marta Robledo
Fatima Said
Tim Schultz
Catherine Yin


 
 
Rohit N. Kulkarni, MD, PhD
Investigator
Joslin Diabetes Center
Core Director: Specialized Assay Core
Joslin Diabetes Center
Associate Professor of Medicine
Harvard Medical School
 
5/1/1997 -  
 
 

POSITIONS: One fellowship is currently available. Letters of inquiry with a short description of career aims can be sent by e-mail to Kelli Parlee.

FUNDING: Research is supported by funding from the National Institutes of Health, the American Diabetes Association and Astra-Zeneca.

CURRENT COLLEAGUES in the Laboratory:



Kelli Parlee: Administrative Co-ordinator
Jane Hu: Lab Manager
Samantha Haring: Research Assistant
Mardelle Rosales: Research Assistant
Ben Hambro: Research Assistant

Jyotsna Shankar: Summer student
Sevim Kahraman: Summer student

Chong Wee Liew: Post-Doctoral Fellow
Ercument Dirice: Post-Doctoral Fellow
Susana Silva: Post-Doctoral Fellow
Abdel El Ouaamari: Post-Doctoral Fellow
Masaru Akiyama: Post-Doctoral Fellow
Helge Rader: Post-doctoral Fellow

DERC SPECIAL ASSAY CORE:

Geetha Sankaranarayanan: Research Assistant
Zhen Fu: Research Assistant


The interests of the KULKARNI LABORATORY are focused around the following specific areas:

1. THE ROLE(S) OF INSULIN/IGF-I SIGNALLING MECHANISMS IN REGULATION OF ISLET CELL GROWTH, APOPTOSIS AND BETA-CELL REPLICATION.

It is evident from several studies, including our own, that insulin and IGF-I signaling play critical roles in the modulation of islet function including glucose sensing of beta cells, protection against beta cell death and in regulating the expression of transcription factors in islet cells. We have created several genetic models to examine the roles of insulin and IGF-1 receptors in islet biology - for example, we have used the Cre-LoxP technique to create tissue-specific insulin receptor and IGF-1 receptor knockouts to complement in vitro models using primary islets from humans and rodents and beta and alpha cell lines derived from the knockouts. Using these powerful and unique reagents we are currently dissecting the cross-talk between insulin, IGF-I and glucose signaling pathways in different islet cell types that express the receptors for insulin and IGF-I. These studies will provide crucial information on potential mechanisms that regulate beta cell death and provide clues to novel, 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 in beta cell growth and apoptosis (ER stress) during embryonic and adult life. We are also using transplantation and parabiotic approaches to complement the in vivo and in vitro studies described above. Together, these studies will provide critical information on islet biology in two major ways - first, it will allow us to gain a deeper insight into the fundamental physiological mechanisms that govern the normal growth and funtioning of pancreatic islets; second, it will provide a physiological basis to explore and identify critical targets in signaling pathways that may be useful to design potential therapeutic strategies to counter beta cell death in transplanted grafts and to plan alternative approaches to generate new beta cells. Finally, these studies will open new avenues to prevent beta cell failure in type 2 diabetes.

2. BETA-CELL STEM CELLS AS A POTENTIAL SOURCE OF REGENERATION.

While there is considerable debate regarding the origin of human and rodent beta cells our studies indicate the presence of potential stem cells within the islet itslef - i.e. "beta-cell" stem cells. To directly address this exciting possibility, we are utilizing several approaches including lineage trace analysis, parabioisis and transplantation techniques in genetically engineered mouse models.

3. THE ROLES OF INSULIN RECEPTOR SUBSTRATE (IRS) PROTEINS IN ISLET FUNCTION AND GENE TRANSCRIPTION.

All four IRS proteins are expressed in islet cells. We are using loss-of-function models, including IRS-1, IRS-2, IRS-3 and IRS-4 knockouts, to examine the role(s) of each substrate and potential compensatory effects of other substrates in islet alpha and beta cell function. The availability of these mouse models provides access to normal islet tissue to compare and contrast with findings obtained from siRNA-treated tumor-derived alpha- and beta-cell lines (INS-1, betaTC, MIN6, alphaTC and InRIG etc).

4. MECHANISMS THAT LINK TYPE-2 DIABETES AND OBESITY AT THE LEVEL OF THE ISLET.

Although the high incidence of type 2 diabetes in obese individuals is well documented, the mechanisms that promote islet dysfunction in these individuals are not understood. We propose a potential link between leptin signaling and insulin/IGF-I regulated 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 beta-cell-specific insulin and/or IGF-1 receptor knockouts and leptin receptor (ObRb) knockout mice. A second approach is focused on studying pathways that link leptin/insulin signaling with individual pathways that utilize PPARgamma, PGC1alpha and TRB3 in islets, all of which are important in modulating metabolic processes in other tissues such as the liver.


SELECTED BIBLIOGRAPHY: (For a full list click on CV under Investigator Specifics).

1) Kulkarni RN et al. Cell, 96:329-339, 1999.
2) Kulkarni RN et al. J Clin. Invest, 104:R69-R75, 1999.
3) Flier SN, Kulkarni RN & Kahn CR. Proc. Nat. Acad. Sci. USA., 98:7475-7480, 2001.
4) Kulkarni RN* et al. (*corresponding author). Nat. Genet., 31(1):111-115, 2002.
5) Kulkarni RN. Biochem. Soc. Transac. 30(2):317-322, 2002.
6) Kulkarni RN & Kahn CR. Science, 303:1311-1312,2004.
7) Goren HJ, Kulkarni RN & Kahn CR. Endocrinology, 145:3307-3323, 2004
8) Kulkarni RN* et al (*corresponding author). Diabetes, 53:1517-25, 2004
9) Koo S-H, Satoh H, Herzig S, Lee C-H, Hedrick S, Kulkarni RN, Evans R, Olefsky J, Montminy M. Nat Med, 10:530-534, 2004
10) Kulkarni RN* et al. (*corresponding author). J Clin. Invest, 114:828-836, 2004
11) Bates SH, Kulkarni RN, Seifert M & Myers MG. Cell Metabolism, 1(3):169-178, 2005
12) Hennige, AM, Ozcan U, Okada T, Jhala U, ... White MF, Kulkarni RN. Am J Physiol Endocrinol Metab, 289:E337-E346, 2005.
13) Gunton JE, Kulkarni RN, Yim SH, Okada T, et al. Cell, 122:337-349, 2005.
14) Kulkarni RN. Insulin action in the islet b-cell. In Saltiel, A & Pessin, J.E. eds. Mechanisms of Insulin Action. Eurekah, Landes Biosciences;ISBN:1-58706-252-6, 2005.
15) Ueki K, Okada T, Hu J, Liew CW, Assmann A,..., Kulkarni RN. Nat Genetics, 38(5):583-588, 2006. Papers of Note. Sci. Aging Knowl. Environ. 2006(8).
16) Qi L, Heredia J, Altarejos JY, Screaton R, .....Liew CW, Kulkarni RN,...Montminy M. Science, 312(5781):1763-1766, 2006.
17) Wang L, Huang J, Saha P, Kulkarni RN, ..., Moore DD. Mol Endocrinol.,20(11):2671-2681, 2006
18) Koh HJ, Arnolds DE, Fujii N, .... Kulkarni RN, Kahn CR, Goodyear LJ.Mol Cell Biol.26(22):8217-8227, 2006
19) Pissios P, Ozcan U, Kokkotou E, Okada T, Liew CW, Liu S,......Maratos-Flier E & Kulkarni RN. Diabetes56:311-319, 2007
20) Okada T, Liew CW, Hu, J, Hinault C,... Stoffel M, Kulkarni RN. Proc Natl Acad Sci USA 2007 doi/10.1073/pnas.0608703104.
21) Morioka T, Asilmaz E, Hu J, Dishinger JF, ... Elmquist JK, Kennedy RT, Kulkarni RN. J Clin Invest 117(10):2860-2868, 2007
22) Handschin C, Choi CS, Chin S, Kim S, Kawamori D,..., Kulkarni RN, Shulman GI, Spiegelman BC. J Clin Invest117(11):3463-3474, 2007
23) Hinault C,... Kulkarni RN. Diab Obes Metab 2008 10 Suppl 4:136-46.
24) Peytuk VA, Qian WJ, Hinault C, .... Kulkarni RN, Smith RD. J Proteom Res 7(8):3114-26, 2008.
250 Tseng YH.... Kulkarni RN, Kahn CR. Nature, 454(7207):1000-4, 2008.
25) Deangelis AM, ... Kulkarni RN, Kim SK, Najjar SM. Diabetes 2008 Epub June 10
26) Assmann A, Hinault C, Kulkarni RN. Pediatric Diabetes 2008 Epub Sep 19
27) Welters H, Kulkarni RN. Trends Endocrinol Metab 2008 Epub Oct 14
28) Hisanaga E.... Kukarni RN, Mori M, Kojima I. Diabetes 2009 Epub Nov 4
29) Torii S.,... . Kulkarni, R. N., Takeuchi, T. Diabetes 2009.
30) Assmann A., ... Kulkarni, R.N. Mol Cell Biol 2009.
31) Kawamori D.,.... Kulkarni, R.N. Cell Metabolism 2009.
32) Kawamori D, Kulkarni, R.N. Islets 2009.
33) Liu S., ... Kulkarni, R.N. PLoS One 2009.
34) Zhang Z., ... Kulkarni, R.N., Stanton R.C. FASEB J 2009.
35) Senta G., Hinault C.,... Kulkarni,R.N. Diabetes 2010.

BIOGRAPHICAL SKETCH:

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. 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 working on 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 2007 Endocrine Society Ernst Oppenheimer Laureate Award for Outstanding Work by a Young Investigator, elected to the American Society for Clinical Investigation in April 2007, and recipient of the 2010 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.