Diabetes mellitus is a lifelong chronic disease with worldwide prevalence estimated at 180 million patients in 2007. The importance of transcription factors in the etiology of diabetes is exemplified by the fact that five of the six known forms of monogenic diabetes (MODY) result from mutations in genes encoding these factors. Recent genome-wide associations studies have identified multiple loci, or genomic regions, that are associated with type 2 diabetes;however, the mechanisms behind the associations of these new gene variants and disease have yet to be determined. This is of particular importance for a region on chromosome 10, because in this case three genes are in the same haplotype block and thus inherited together: HHEX (Hematopoietically expressed homeobox), KIF11 (kinesin-interacting factor 11) and IDE (insulin-degrading enzyme). Therefore, we will investigate the contribution of the mouse Hhex gene to endocrine pancreas differentiation and 2-cell function using genetic and genomic means. In addition, we will extend our work on transcriptional regulation of pancreatic development and function through conditional gene ablation of CREB, for which existing data are controversial.
Our specific aims are:
In specific Aim 1, we will determine the contribution of Hhex to pancreas development and differentiation using conditional gene ablation and genome- wide location analysis.
In Aim 2, we will delineate the role of Hhex in function and proliferation of the mature 2-cell using multiple physiological, biochemical and molecular approaches.
In Aim 3, we will investigate how the cAMP- responsive transcription factor CREB controls stimulus-secretion coupling and the 2-cells response to incretins using cell-type and inducible gene deletion.

Public Health Relevance

Diabetes is a significant health problem, affecting more than 20 million people in the United States. Failure of the insulin-producing beta-cell to keep up with the body's need for insulin is a major contributor to diabates. The molecular mechanisms that regulate beta-cell proliferation and function are far from being understood completely. Therefore, we will develop and exploit new genetic tools to elucidate fundamental questions regarding the function of transcriptional regulators, or master genes, in proliferation and performance of beta-cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK055342-15
Application #
8507213
Study Section
Special Emphasis Panel (ZRG1-DKUS-G (03))
Program Officer
Sato, Sheryl M
Project Start
1998-09-30
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
15
Fiscal Year
2013
Total Cost
$385,333
Indirect Cost
$141,208
Name
University of Pennsylvania
Department
Genetics
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Zhang, Jia; McKenna, Lindsay B; Bogue, Clifford W et al. (2014) The diabetes gene Hhex maintains ?-cell differentiation and islet function. Genes Dev 28:829-34
Santos, Gustavo Jorge Dos; Ferreira, Sandra Mara; Ortis, Fernanda et al. (2014) Metabolic memory of ß-cells controls insulin secretion and is mediated by CaMKII. Mol Metab 3:484-9
Jiao, Yang; Rieck, Sebastian; Le Lay, John et al. (2013) CISH has no non-redundant functions in glucose homeostasis or beta cell proliferation during pregnancy in mice. Diabetologia 56:2435-45
Schaffer, Ashleigh E; Taylor, Brandon L; Benthuysen, Jacqueline R et al. (2013) Nkx6.1 controls a gene regulatory network required for establishing and maintaining pancreatic Beta cell identity. PLoS Genet 9:e1003274
Bramswig, Nuria C; Kaestner, Klaus H (2012) Organogenesis and functional genomics of the endocrine pancreas. Cell Mol Life Sci 69:2109-23
Cui, Chang-Yi; Childress, Victoria; Piao, Yulan et al. (2012) Forkhead transcription factor FoxA1 regulates sweat secretion through Bestrophin 2 anion channel and Na-K-Cl cotransporter 1. Proc Natl Acad Sci U S A 109:1199-203
Gao, Nan; Le Lay, John; Qin, Wei et al. (2010) Foxa1 and Foxa2 maintain the metabolic and secretory features of the mature beta-cell. Mol Endocrinol 24:1594-604
May, Catherine Lee; Kaestner, Klaus H (2010) Gut endocrine cell development. Mol Cell Endocrinol 323:70-5
Bhandare, Reena; Schug, Jonathan; Le Lay, John et al. (2010) Genome-wide analysis of histone modifications in human pancreatic islets. Genome Res 20:428-33
Kaestner, Klaus H (2010) The FoxA factors in organogenesis and differentiation. Curr Opin Genet Dev 20:527-32

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