(taken from the application) The applicant proposes a series of studies designed to enhance and extend ongoing investigation under the auspices of the parent K08 award, 5 K08 DKO2476-03. This small grant, if awarded, is intended to run concurrently with the final two years of the K08 award and would provide additional resources to facilitate the transition of the principal investigator to independent investigator. Evidence from studies of insulin gene transcription, pancreatic development and human genetics has converged to identify transcription factors in the pancreatic beta cell as critical mediators of normal glucose homeostasis. The pancreas-specific homeoprotein IDX-1 is an essential factor in the development of the pancreas, a major regulator of insulin gene transcription and a target for mutations in diabetes mellitus in humans. The proposed studies will test the hypothesis that IDX-1 is a fundamental and critical regulator of glucose-mediated transcriptional expression of the insulin gene in the beta cells of the endocrine pancreas. IDX-1 may also be essential for the maintenance of pancreatic beta cell mass. Defective regulation of the homeoprotein IDX-1 by prolonged exposure to high levels of glucose may explain the impairment of insulin production characteristically seen in patients with non insulin dependent diabetes mellitus. Further, it is proposed that interaction of IDX-1 with other coactivator proteins regulates activation of insulin gene transcription.
The aims of the proposed studies are: 1) to identify coactivator proteins that interact with IDX-1 in pancreatic beta cells; 2) to determine whether IDX-1 interaction with coactivator proteins alters activation of insulin gene transcription; and 3) to study effects of IDX-1 inactivation on glucose-mediated regulation of insulin gene transcription. Elucidation of molecular mechanisms of the regulation and functions of IDX-1 may provide key insights central to the development of new strategies for the treatment of patients with diabetes mellitus.
| Volinic, Jamie L; Lee, Jee H; Eto, Kazuhiro et al. (2006) Overexpression of the coactivator bridge-1 results in insulin deficiency and diabetes. Mol Endocrinol 20:167-82 |
| Stanojevic, Violeta; Habener, Joel F; Thomas, Melissa K (2004) Pancreas duodenum homeobox-1 transcriptional activation requires interactions with p300. Endocrinology 145:2918-28 |
| Thomas, M K; Devon, O N; Lee, J H et al. (2001) Development of diabetes mellitus in aging transgenic mice following suppression of pancreatic homeoprotein IDX-1. J Clin Invest 108:319-29 |
| Hamza, I; Faisst, A; Prohaska, J et al. (2001) The metallochaperone Atox1 plays a critical role in perinatal copper homeostasis. Proc Natl Acad Sci U S A 98:6848-52 |
