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.
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.
|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|
|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|
|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 * (ERR*). J Biol Chem 288:25007-24|