Human beta-cells have an extremely low mitotic index, even compared with rodent beta-cells. Furthermore, efforts to stimulate proliferation in vitro result in the rapid shut off of insulin gene expression. The molecular mechanism that mediates the inverse relationship between growth and maintenance of a fully differentiated state is poorly understood, but if clarified could be exploited to induce beta-cell replication for diabetes therapy. Cyclin-dependent kinase inhibitors (CDKIs) play key roles in controlling cell cycle entry. In the human islet, microarray analysis has found that only two CDKIs, p57Kip2 and P21Cip1, are expressed at high levels. P57Kip2 is specific to beta-cells in the adult human pancreas and mutational loss of p57Kip2 expression in human patients results in beta-cell hyperplasia. Thus, p57Kip2 is an excellent target for interventions designed to promote beta-cell replication. In this proposal, we will take advantage of human pancreatic endocrine cell lines that inducibly express the cyclin dependent kinase inhibitor p57Kip2 to develop a high-throughput screen for compounds that modulate cell cycle entry and p57Kip2 transcription. Small molecule hits will serve as probes to study p57Kip2 regulation and potentially as lead candidates for development of diabetes therapeutics. By furthering our understanding of the mechanisms that control cell cycle entry in human beta-cells, we should be in an improved position to induce beta-cell regeneration in vivo and/or in vitro.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
7R21NS057001-02
Application #
7656976
Study Section
Special Emphasis Panel (ZNS1-SRB-G (05))
Program Officer
Scheideler, Mark A
Project Start
2006-09-05
Project End
2008-08-31
Budget Start
2008-04-01
Budget End
2008-08-31
Support Year
2
Fiscal Year
2006
Total Cost
$39,471
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Kiselyuk, Alice; Farber-Katz, Suzette; Cohen, Tom et al. (2010) Phenothiazine neuroleptics signal to the human insulin promoter as revealed by a novel high-throughput screen. J Biomol Screen 15:663-70
Zhang, Sharon S; Hao, Ergeng; Yu, Jianxiu et al. (2009) Coordinated regulation by Shp2 tyrosine phosphatase of signaling events controlling insulin biosynthesis in pancreatic beta-cells. Proc Natl Acad Sci U S A 106:7531-6