This application focuses on the long term goal of stimulating ?-cell regeneration as a cure for diabetes. The mechanism controlling the cell cycle progression of ?-cells keeps them at an extremely low proliferating state that decreases further with age. Using a model that we have previously shown to exhibit enhanced ?-cell regeneration, we plan to test the hypothesis that p16 and cyclin D are responsible for the observed slow regeneration phenotype. PTEN (phosphatase and tensin homologue deleted on chromosome 10) is a negative regulator of a particular ?-cell mitogenic signal, PI3K/AKT. We have shown that loss of PTEN in ?- cells leads to increased islet mass and mitotic activity. To evaluate the molecular mechanisms responsible for this phenotype, we explored various cell cycle regulators and discovered that cyclin D and p16 are significantly altered in the islets. We followed this initial observation and confirmed that PTEN can directly regulate p16 and cyclin D using a glioma cell line. Because of the correlation of p16 upregulation with loss of regeneration in aged ?-cells, we hypothesized that PTEN loss may be capable of inducing regeneration of ?- cells in even older mice. Our preliminary data showed that this is possible in adult mice without the contribution of developmental deletion of Pten. To demonstrate this result, we employed a model that can induce the deletion of Pten in adult mice. Together, these data led to the current hypothesis that PTEN regulates regeneration of b-cells through p16 and cyclin D. To test this hypothesis, we have planned three specific aims: First, we will investigate whether the mitotic activity in ?-cells induced by PTEN loss depends on p16 and cyclin D. Second, we will determine if loss of PTEN is capable of inducing regeneration of ?-cells in mice beyond the age (1 year) at which physiological stimuli can no longer enhance ?-cell regeneration. Third, we will determine whether PTEN regulates p16 through PI3K/AKT signaling. The results from this analysis will substantially improve the understanding of how ?-cells regenerate and shed light on what molecules need to be manipulated to promote their regeneration.

Public Health Relevance

Diabetes is caused by the loss or degradation of beta-cells in the pancreas. Normally, beta-cells are replaced very slowly in adults. The goal of this proposal is to identify ways of speeding up the replacement of beta-cells in order to cure Diabetes.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DK084241-05
Application #
8691795
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Sato, Sheryl M
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Southern California
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90089