Understanding the molecular mechanisms governing beta cell proliferation has important ramification for fostering beta cell regeneration and the treatment of diabetes. Studies supported by a pilot 2 year collaborative grant established that cyclin D2-mediated proliferation was essential in the regulation of postnatal beta cell mass. We also demonstrated that the transition of beta cells from quiescence to proliferation is controlled by p27, a negative regulator of cyclin D2-mediated proliferation. We showed that quiescent beta cells accumulate p27 and disabling ? p27 in these cells allows them to divide. Thus, the cellular abundance of p27 is a critical determinant of whether a beta cell divides or remains quiescent. We now present preliminary data to demonstrate that ubiquitin ligase-mediated degradation pathways regulate the cellular abundance of p27 and the progression of beta cell proliferation. We also show that pathways regulating p27 turnover could be involved in accumulating p27 in beta cells of animal models of type 2 diabetes. In the next five years we will endeavor to integrate mechanisms of p27 turnover and their role in metabolic disorders. We propose to study:
Aim 1, the ubiquitin ligase-mediated degradation pathways that regulate cell cycle progression of beta cells and their role in beta cell compensatory growth in insulin resistance animal models;
in Aim 2, to utilize p27 degradation pathways to promote beta cell expansion/regeneration; ? Aim 3, how p27 degradation pathways contribute to beta cell failure during the development of type 2 diabetes in animal models;
Aim 4, to examine whether targeting p27 could be beneficial for cell-based therapies in which the extent of cell proliferation could have potential benefit. These studies will be carried out using null mouse mutants, beta cell-specific inducible transgenic mice, and cultured islet, using methods that are fully implemented in the laboratory. The goal of this work is to find a therapeutic approach for modifying p27 function and we hope that by identifying mechanisms of p27 turnover, new ways to modulate its function in a controlled fashion can be found. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK068763-03
Application #
7145759
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Sato, Sheryl M
Project Start
2004-07-05
Project End
2010-06-30
Budget Start
2006-07-15
Budget End
2007-06-30
Support Year
3
Fiscal Year
2006
Total Cost
$285,825
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Dhawan, Sangeeta; Tschen, Shuen-Ing; Zeng, Chun et al. (2015) DNA methylation directs functional maturation of pancreatic ? cells. J Clin Invest 125:2851-60
Kanji, Murtaza S; Martin, Martin G; Bhushan, Anil (2013) Dicer1 is required to repress neuronal fate during endocrine cell maturation. Diabetes 62:1602-11
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Zhou, Josie X; Dhawan, Sangeeta; Fu, Hualin et al. (2013) Combined modulation of polycomb and trithorax genes rejuvenates ? cell replication. J Clin Invest 123:4849-58
Georgia, Senta; Kanji, Murtaza; Bhushan, Anil (2013) DNMT1 represses p53 to maintain progenitor cell survival during pancreatic organogenesis. Genes Dev 27:372-7
Tschen, Shuen-Ing; Georgia, Senta; Dhawan, Sangeeta et al. (2011) Skp2 is required for incretin hormone-mediated ?-cell proliferation. Mol Endocrinol 25:2134-43
Dhawan, Sangeeta; Georgia, Senta; Tschen, Shuen-Ing et al. (2011) Pancreatic ? cell identity is maintained by DNA methylation-mediated repression of Arx. Dev Cell 20:419-29
Papizan, James B; Singer, Ruth A; Tschen, Shuen-Ing et al. (2011) Nkx2.2 repressor complex regulates islet ?-cell specification and prevents ?-to-?-cell reprogramming. Genes Dev 25:2291-305
Georgia, Senta; Hinault, Charlotte; Kawamori, Dan et al. (2010) Cyclin D2 is essential for the compensatory beta-cell hyperplastic response to insulin resistance in rodents. Diabetes 59:987-96

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