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Arun J. Sharma, Ph.D.

Dr. Sharma is an Investigator in the Section on Islet Transplantation and Cell Biology at Joslin and an Assistant Professor of Medicine at Harvard Medical School. He received his doctoral degree in Microbiology from the University of Baroda, India, and completed postdoctoral training in Microbiology at the University of Tennessee in Knoxville, and in Molecular Physiology and Biophysics at Vanderbilt University. In 1998, Dr. Sharma received a Career Development Award from the American Diabetes Association.

Dr. Sharma focuses on understanding the molecular mechanisms regulating the development and differentiation of beta cells and the development of beta-cell dysfunction in diabetes. Dr. Sharma’s research is important for both type 1 and type 2 diabetes, contributing newer transplantable sources of insulin-producing cells and helping to overcome beta-cell dysfunction.

A major accomplishment of the Sharma laboratory is the identification and cloning of an elusive insulin gene-transcription factor, MafA, which plays a critical role in the selective expression of insulin in beta cells and in regulating insulin expression in response to changes in glucose concentrations. Dr. Sharma’s laboratory studies the role of MafA in beta-cell function and how its absence leads to beta-cell dysfunction. Results demonstrate that MafA is required for the survival of beta cells and for their ability to secrete insulin.

During embryonic development, a related Maf factor, MafB, is expressed first in beta-cell precursors followed by induction of MafA and maturation of beta cells. Thus, cloning of the MafA factor is a major breakthrough in developing strategies for the production of glucose-responsive cells that secrete insulin. Consequently, Dr. Sharma and his colleagues are studying the role of MafA and related Maf factors in pancreatic development and differentiation of beta cells. Results from these studies will be critical in determining how MafA can differentiate pancreatic precursors and other cells into beta cells.

An obstacle to treating type 1diabetes is the current shortage of glucose-responsive insulin-producing cells for transplantation. The most promising approach for obtaining these cells is to differentiate embryonic and adult stem/precursor cells into beta cells. To this end, Dr. Sharma’s research includes studying differentiation of embryonic stem cells and pancreatic ductal cells into beta cells.

One goal is to identify and clone the transcription factors that regulate the formation of pancreatic ductal cells and their redifferentiation into insulin-producing cells. Results from this study may lead to new strategies for directing the expression of key transcription factors (including MafA) to differentiate pancreatic ductal and adult or embryonic stem cells into insulin-producing cells. Ongoing studies yield new tools for gene therapies to modify pancreatic stem/precursor cells and could lead to the formation of beta cells with characteristics such as resistance to immune assault and glucose toxicity—providing newer, more powerful therapies for diabetes.

Selected References
Nishimura W, Kondo T, Salameh T, El Khattabi I, Dodge R, Bonner-Weir S, Sharma A. A switch from MafB to MafA expression accompanies differentiation to pancreatic beta-cells. Devl Biol 293:526-539, 2006.

Bonner-Weir S, Sharma A. Are there pancreatic progenitor cells from which new islets form after birth? Nat Clin Pract Endocrinol Metab 2006, in press.

Nishimura W, Salameh T, Kondo T, Sharma A. Regulation of insulin gene expression by overlapping DNA-binding elements. Biochem J 392:181-189, 2005.

Bonner-Weir S, Toschi E, Inada A, Reitz P, Fonseca SY, Aye T, Sharma A. The pancreatic ductal epithelium serves as a potential pool of progenitor cells. Pediatr Diabetes 5(Suppl 2):16-22, 2004.

Olbrot M, Rud J, Moss LG, Sharma A. Identification of ß-cell-specific insulin gene transcription factor RIPE3b1 as mammalian MafA. Proc Natl Acad Sci U S A 99:6737-6742, 2002.

Harrington RH, Sharma A. Transcription factors recognizing overlapping C1-A2 binding sites positively regulate insulin gene expression. J Biol Chem 276:104-113, 2001.