Arun Sharma, Ph.D.
The main focus of my research laboratory is to understand the role of Maf factors in regulating specification and maturation of β-cells. Our earlier research on determining the molecular mechanisms regulating glucose-responsive expression of insulin gene led to our identification of the novel transcription factor MafA. This was the first reported identification and cloning of MafA in the mammalian system, and the first proof for the role of the Maf family of transcription factors in regulating beta cell function. In addition, based on our characterization of the expression patterns of the Maf family of transcription factors, we were the first to provide evidence that insulin-producing cells formed during embryonic development undergo maturation that involves a switch in Maf factor expression, leading to their conversion into glucose-responsive β-cells. These results formed the basis to examine not only the mechanisms regulating specification of β-cells, but also to map the process regulating their maturation. Hence, our primary research goal has been to delineate the pathways regulating specification of insulin-producing cells during development and their maturation into glucose responsive β-cells. In addition, we are interested in examining the pathways required for maintaining the glucose-responsiveness and functional capacity of adult β-cells. Understanding these processes will provide improved methods to generate glucose-responsive β-cells and to overcome β-cell dysfunction, as novel therapies for diabetes.
The current areas of research include:
(1) Examine the molecular mechanisms underlying the proliferation and differentiation of endocrine progenitors into β-cells: We are currently examining the role of the transcription factor Ovol1, and those of Maf factors, in regulating pancreatic development and differentiation of endocrine cells. The transcription factor Ovol1 has been reported in other systems to regulate the balance between proliferation and differentiation of progenitor cells. We recently demonstrated that the Ovol1 is a direct downstream target of Neurogenin 3 (Ngn3), a gene that controls the formation of all endocrine cell types. We are using several approaches, including alteration in the expression of Ovol1, to examine the role of this factor in regulating the balance between the proliferation and differentiation of Ngn3-expressing endocrine progenitors, as well as the role of Ovol1 in pancreatic development.
Our study on the role of Maf factors in embryonic development is based on the hypothesis that the primary role of MafA is to regulate maturation of β-cells, while that of other Maf factors is to regulate the specification of endocrine cells. We have generated several animal models to alter the expression of Maf factors during pancreatic development to regulate the specification of endocrine cells. Our on-going work focuses on mapping the role of these factors in regulating the specification of insulin-producing cells and their subsequent maturation into glucose-responsive β-cells.
(2) Examine the importance of MafA in maintaining/enhancing β-cell function after birth: Increasing evidence supports a role of MafA in regulating glucose-responsiveness of β-cells. Our hypothesis has been that MafA is essential for maintaining glucose-responsiveness of β-cells, and enhancing its function would overcome β-cell dysfunction and diabetes. We are examining how MafA expression regulates glucose-responsiveness of β-cells, and how its’ expression is altered under diabetic conditions. In addition, we are studying the role of other factors in regulating expression of MafA as well as in the maturation of β-cells. Another research objective of our group has been to evaluate the therapeutic potential of MafA in overcoming β-cell dysfunction.
(3) Develop novel strategies to regulate MafA expression in β-cells: Several molecular and cellular approaches are being used to examine the mechanisms regulating the expression and stability of MafA. The objective underlying these studies is to identify the molecular mechanisms that selectively regulate the expression of MafA in β-cells and use these mechanisms to develop ways to enhance MafA expression. These studies are designed to complement our in vivo analysis of the MafA, and to ultimately develop ways to generate glucose-responsive β-cells and to overcome β-cell dysfunction.
Dr. Sharma is an investigator in the Section on Islet Cell Biology and Regenerative Medicine at Joslin and Assistant Professor of Medicine at Harvard Medical School. Dr. Sharma received his doctorate in microbiology at MS University of Baroda, India, and then completed postdoctoral training in transcriptional regulation of gene expression at UT Knoxville and Vanderbilt University. He is a recipient of the Career Development Award from the American Diabetes Association. He is or has been a member of the grant review panels for the NIH, Juvenile Diabetes Research Foundation and the American Diabetes Association.