My goal as a physician-scientist is to improve the lives of children through research on the pathophysiology of diabetes mellitus. To this end I have spent the past several years training in the laboratory of Dr Morris White investigating the etiology of beta-cell dysfunction in diabetes. This proposal will allow me to further train in cell biology and physiology as I transition to a career as an independently funded investigator in the Joslin Diabetes Center. Little is known about the regulation of beta-cell proliferation, although the insulin-like growth factors (IGFs), other growth factors, and the pancreatic transcription factor Pdx1 may play a role. Insulin Receptor Substrate (IRS)-2 related pathways are essential for beta-cell survival: Irs2 knockout (-/-) mice develop beta-cell failure and insulin resistance resulting in death from diabetes. I have previously shown that Irs2 signaling alters levels of Pdx1, a pancreatic transcription factor that promotes beta-cell mass and function. I also found that Pdx1 overexpression can stimulate beta-cell proliferation in mice, as measured by BrdU incorporation into beta-cells. In most tissues mitogenic stimuli increase gene expression of G1 cyclin D-type cyclins, which partner with cyclin dependent kinase (cdk)-4 or -6 to promote cell growth. Remarkably, cdk4-/- mice develop diabetes from inadequate beta-cell growth. From these findings I suspected that one of the D-type cyclins might be an important partner of cdk4 in islet expansion. Supporting this notion I have recently found that cyclin D2-/- mice develop diabetes with impaired beta-cell growth. Further experiments suggest that Pdx1 could regulate beta-cell proliferation by directly binding to the cyclin D2 promoter. This proposal will test the hypothesis that cyclin D2 is essential for normal islet growth and that Pdx1 regulates beta-cell proliferation by regulating cyclin D2 activity by examining the following specific aims: 1. To test if cyclin D2 is an essential regulator of islet growth. 2. To test if Pdx1 influences beta-cell proliferation by regulating cyclin D2.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
7K08DK064101-02
Application #
6861567
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
2004-01-01
Project End
2008-09-29
Budget Start
2004-01-01
Budget End
2004-09-29
Support Year
2
Fiscal Year
2003
Total Cost
$102,511
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Sartori, Daniel J; Wilbur, Christopher J; Long, Simon Y et al. (2014) GATA factors promote ER integrity and ?-cell survival and contribute to type 1 diabetes risk. Mol Endocrinol 28:28-39
Kushner, Jake A (2013) The role of aging upon ? cell turnover. J Clin Invest 123:990-5
Rankin, Matthew M; Wilbur, Christopher J; Rak, Kimberly et al. (2013) ?-Cells are not generated in pancreatic duct ligation-induced injury in adult mice. Diabetes 62:1634-45
Kushner, Jake A (2012) Development. Esophageal stem cells, where art thou? Science 337:1051-2
He, Lu Mei; Sartori, Daniel J; Teta, Monica et al. (2009) Cyclin D2 protein stability is regulated in pancreatic beta-cells. Mol Endocrinol 23:1865-75
Rankin, Matthew M; Kushner, Jake A (2009) Adaptive beta-cell proliferation is severely restricted with advanced age. Diabetes 58:1365-72
Teta, Monica; Rankin, Matthew M; Long, Simon Y et al. (2007) Growth and regeneration of adult beta cells does not involve specialized progenitors. Dev Cell 12:817-26
Sherry, Nicole A; Kushner, Jake A; Glandt, Mariela et al. (2006) Effects of autoimmunity and immune therapy on beta-cell turnover in type 1 diabetes. Diabetes 55:3238-45
Kushner, Jake A (2006) Beta-cell growth: an unusual paradigm of organogenesis that is cyclin D2/Cdk4 dependent. Cell Cycle 5:234-7
Kushner, Jake A; Simpson, Laura; Wartschow, Lynn M et al. (2005) Phosphatase and tensin homolog regulation of islet growth and glucose homeostasis. J Biol Chem 280:39388-93

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