The mechanism of beta-cell regeneration

描述（由申请人提供）：本申请的重点是刺激细胞再生作为治疗糖尿病的长期目标。控制细胞周期进程的机制使它们保持在极低的增殖状态，并随着年龄的增长而进一步降低。使用一个模型，我们以前已经显示出增强的细胞再生，我们计划测试的假设，p16和细胞周期蛋白D是负责观察到的缓慢再生表型。PTEN（10号染色体上缺失的磷酸酶和张力蛋白同源物）是一种特定的细胞有丝分裂信号PI 3 K/AKT的负调节因子。我们已经证明，在胰岛细胞中PTEN的缺失导致胰岛质量和有丝分裂活性的增加。为了评估这种表型的分子机制，我们探索了各种细胞周期调节因子，发现细胞周期蛋白D和p16在胰岛中发生了显着改变。我们遵循这一初步观察，并证实，PTEN可以直接调节p16和细胞周期蛋白D使用胶质瘤细胞系。由于p16上调与衰老的<$-细胞再生丧失的相关性，我们假设PTEN的丧失可能能够诱导衰老小鼠<$-细胞的再生。我们的初步数据表明，这是可能的，在成年小鼠没有发展的Pten缺失的贡献。为了证明这一结果，我们采用了一种可以诱导成年小鼠Pten缺失的模型。总之，这些数据导致了目前的假设，即PTEN通过p16和细胞周期蛋白D调节b细胞的再生。为了验证这一假设，我们计划了三个具体的目标：首先，我们将研究PTEN缺失诱导的细胞有丝分裂活性是否依赖于p16和细胞周期蛋白D。第二，我们将确定PTEN的缺失是否能够诱导超过生理刺激不再能增强<$-细胞再生的年龄（1岁）的小鼠<$-细胞再生。第三，我们将确定PTEN是否通过PI 3 K/AKT信号转导调节p16。这项分析的结果将大大提高对细胞如何再生的理解，并阐明需要操纵哪些分子来促进它们的再生。 公共卫生相关性：糖尿病是由胰腺中β细胞的损失或降解引起的。正常情况下，β细胞在成年人中的替换非常缓慢。该提案的目标是确定加速β细胞替代的方法，以治愈糖尿病。

DESCRIPTION (provided by applicant): 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.