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)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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
2010-08-05
Project End
2015-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
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
He, Lina; Gubbins, James; Peng, Zhechu et al. (2016) Activation of hepatic stellate cell in Pten null liver injury model. Fibrogenesis Tissue Repair 9:8
Bayan, Jennifer-Ann; Peng, Zhechu; Zeng, Ni et al. (2015) Crosstalk Between Activated Myofibroblasts and β Cells in Injured Mouse Pancreas. Pancreas 44:1111-20
Chen, Wan-Ting; Tseng, Chun-Chih; Pfaffenbach, Kyle et al. (2014) Liver-specific knockout of GRP94 in mice disrupts cell adhesion, activates liver progenitor cells, and accelerates liver tumorigenesis. Hepatology 59:947-57
Yang, Kai-Ting; Bayan, Jennifer-Ann; Zeng, Ni et al. (2014) Adult-onset deletion of Pten increases islet mass and beta cell proliferation in mice. Diabetologia 57:352-61
Chen, W-T; Zhu, G; Pfaffenbach, K et al. (2014) GRP78 as a regulator of liver steatosis and cancer progression mediated by loss of the tumor suppressor PTEN. Oncogene 33:4997-5005
Zeng, Ni; Yang, Kai-Ting; Bayan, Jennifer-Ann et al. (2013) PTEN controls β-cell regeneration in aged mice by regulating cell cycle inhibitor p16ink4a. Aging Cell 12:1000-11
Li, Yang; He, Lina; Zeng, Ni et al. (2013) Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) signaling regulates mitochondrial biogenesis and respiration via estrogen-related receptor α (ERRα). J Biol Chem 288:25007-24
Li, Chen; Li, Yang; He, Lina et al. (2013) PI3K/AKT signaling regulates bioenergetics in immortalized hepatocytes. Free Radic Biol Med 60:29-40
Moon, Byoung C; Hernandez-Ono, Antonio; Stiles, Bangyan et al. (2012) Apolipoprotein B secretion is regulated by hepatic triglyceride, and not insulin, in a model of increased hepatic insulin signaling. Arterioscler Thromb Vasc Biol 32:236-46
Zeng, Ni; Li, Yang; He, Lina et al. (2011) Adaptive basal phosphorylation of eIF2α is responsible for resistance to cellular stress-induced cell death in Pten-null hepatocytes. Mol Cancer Res 9:1708-17

Showing the most recent 10 out of 14 publications