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  Joslin Investigator:
   
  
Dr. Arun J. Sharma
 
Investigator Specifics:
Professional Details:
Publications
CV not available

Member of Section:
Islet Transplantation and Cell Biology

Core Director:

Media Core

Current Fellows, Students, or Lab Members:
Ilham El Khattabi, Ph.D.
Kangyi Mao
Wataru Nishimura , M.D.

Past Fellows, etc.:
Rikki Dodge
Takuma Kondo, M.D.
Renee Polcaro


 
 
Arun J Sharma, PhD
Investigator
Joslin Diabetes Center
Assistant Professor of Medicine
Harvard Medical School
 
10/1/1996 -  
 
 Transcription Factors and Pancreatic Development

Diabetes results from reduction in the functional mass of pancreatic beta-cells. Thus, characterizing molecular mechanisms regulating pancreatic regeneration, and development and differentiation of beta-cells is critical for finding cure for diabetes. To this end, we are pursuing two complementary molecular approaches: 1) To characterize the role of transcription factor(s) critical for terminal differentiation event (insulin gene expression) in regulating pancreatic development; and 2) Identify and characterize novel transcription factors regulating differentiation of precursor cells into beta-cells.

Increasing evidence suggest that transcription factors regulating insulin gene expression are key regulators of pancreatic development and differentiation of beta-cells. Transcription factors that bind to three key insulin enhancer elements, E1, A3 and RIPE3b play an important role in beta-cell specific and glucose responsive expression of the insulin gene. Transcription factors binding to the E1 (BETA2) and A3 (PDX-1) elements have been cloned, and their role in pancreatic development and in maturity onset diabetes of young (MODY) further underscores the importance of characterizing factors binding critical insulin enhancer elements. One of the major accomplishments of our research has been the identification and cloning of insulin gene transcription factor that binds the critical RIPE3b element. We demonstrated that the RIPE3b1 factor is a novel mammalian homologue of avian regulator of lens development, MafA. This was the first reported identification of MafA in the mammalian system, and first suggestion for a role of Maf family of transcription factor in regulating beta cell function. Our results suggest that Maf family members are key regulators of differentiation of endocrine precursor into different endocrine cell-types. We are now in the process of characterizing role of MafA and other Maf family members in development, differentiation and function of pancreatic beta-cells.

Intrinsic ability of pancreas to regenerate in response to various physiological and pathological conditions holds the key for developing limitless supply of beta-cells essential for the treatment of Type 1 diabetes. We have demonstrated that the pancreatic ductal epithelium retains the ability to regenerate endocrine, exocrine as well as the ductal cells of the pancreas. We propose to exploit this ability by identifying and characterizing the molecular mechanisms regulating differentiation of endocrine precursors into beta-cells. We have identified several genetic markers that are differentially regulated during pancreatic regeneration. We are currently utilizing these markers to map the steps involved in the differentiation of ductal epithelium into endocrine cells. In addition, we aim to identify transcription factors, which in response to regenerative signals differentially regulate expression of these marker genes. We propose that identification and characterization of these transcription factors is key to inducing in vitro and in vivo differentiation of pancreatic precursor cells into beta-cells.


Selected Bibliography

Nishimura W, Bonner-Weir S, Sharma A. Expression of MafA in pancreatic progenitors is detrimental for pancreatic development. Developmental Biology 2009; 333:108-120.

Kondo T, El Khattabi I, Nishimura W, Laybutt DR, Geraldes P, Shah S, King G, Bonner-Weir S, Weir G, Sharma A. p38 MAPK is a major regulator of MafA protein stability under oxidative stress. Molecular Endocrinology 2009; 23:1281-1290.

Inada A, Nienaber C, Katsuta H, Fujitani Y, Levine J, Morita R, Sharma A, Bonner-Weir S. CAII positive pancreatic cells are progenitors for both endocrine and exocrine pancreas after birth revision. PNAS 2008; 105:19915-19919.

Bonner-Weir S, Inada A, Yatoh S, Li WC, Aye T, Toschi E, Sharma A. Transdifferentiation of pancreatic ductal cells to endocrine beta-cells. Biochem Soc Trans. 2008 Jun;36(Pt 3):353-6.

Nishimura W, Rowan S, Salameh T, Mass RL, Bonner-Weir S, Sell SM, Sharma A. Preferential reduction of β-cells derived from Pax6-MafB-Pathway in MafB deficient mice. Developmental Biology, 2008, 314:443-456.

Wang H., Brun T, Kataoka K, Sharma A, Wolheim CB. MafA controls genes implicated in insulin biosynthesis and secretion. Diabetologia 2007, 50: 348-358.

Bonner-Weir S, Sharma A. Are there pancreatic progenitor cells from which new islets form after birth? Nature Clinical Practice Endocrinology & Metabolism 2006, 2(5): 240-241.

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 of pancreatic β-cells. Developmental Biology 2006, 293:526-539.

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

Bonner-Weir S, Toschi E, Inada A, Reitz P, Fonseca SY, Aye T, Sharma A. Stem Cells and Diabetes. Pediatric Diabetes. 2004; 5:16-22.

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

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

Bonner-Weir S, Sharma A. Pancreatic stem cells. J. Pathol. 2002; 197:519-526.

Sharma A, Zangen DH, Reitz P, Taneja M, Lissauer ME, Miller CP, Weir GC, Habener JF, Bonner-Weir S. The homeodomain protein IDX-1 increases after an early burst of proliferation during pancreatic regeneration. Diabetes 1999;48:507-513.

Sharma A, Olson LK, Robertson RP, Stein R. The reduction of insulin gene transcription in HIT T-15 b cells chronically exposed to high glucose concentration is associated with the loss of RIPE3b1 and STF-1 transcription factor. Mol Endo 1995;9:1127-1134.

Sharma A and Stein R. Glucose-induced transcription of the insulin gene is mediated by factors required for beta-cell-type specific expression. Mol. Cell. Biol. 1994;14:871-879.