The mechanism of beta-cell regeneration

β细胞再生机制

基本信息

批准号：
8479350
负责人：
Bangyan Stiles
金额：
$ 27.08万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-05 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8479350
关键词：
1 year old 6 year old AKT1 gene Address Adult Age Age-Months Animals Beta Cell Cell Aging Cell Cycle Cell Cycle Progression Cell Proliferation Cells Chromosomes, Human, Pair 10 Cyclin D1 Data Development Diabetes Mellitus Down-Regulation Exhibits Figs - dietary Goals Homologous Gene Injection of therapeutic agent Insulin Signaling Pathway Light Mediating Mitotic Activity Modeling Molecular Molecular Analysis Mus Mutant Strains Mice Natural regeneration Null Lymphocytes PI3K/AKT PTEN gene Pancreas Pathway interactions Patients Phenotype Phosphoric Monoester Hydrolases Physiological Proliferating Proto-Oncogene Proteins c-akt Regulation Research Role Signal Transduction Speed Stimulus Tamoxifen Testing Up-Regulation aged beta cell replacement design glioma cell line improved islet middle age mutant overexpression public health relevance research study senescence tensin

项目摘要

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.

描述（由申请人提供）：本申请侧重于刺激 ¿ -细胞再生作为糖尿病的治疗方法。控制细胞周期进展的机制。 -细胞使它们保持在极低的增殖状态，并且随着年龄的增长而进一步减少，使用我们之前展示的增强的模型。 -细胞再生，我们计划测试以下假设：p16 和细胞周期蛋白 D 负责观察到的缓慢再生表型 PTEN（10 号染色体上删除的磷酸酶和张力蛋白同源物）是特定 ¿ 的负调节因子。 -细胞有丝分裂信号，PI3K/AKT 我们已经证明 ¿ 中 PTEN 的丢失。 - 细胞导致胰岛质量和有丝分裂活性增加。为了评估导致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 在胰岛中显着改变。我们遵循了这一初步观察并证实了 PTEN。可以使用神经胶质瘤细胞系直接调节 p16 和细胞周期蛋白 D，因为 p16 上调与老年人再生能力丧失相关。 -细胞，我们培育出 PTEN 丢失可能能够诱导 ¿ -甚至在老年小鼠中的细胞。我们的初步数据表明，在没有 Pten 发育缺失的情况下，这也是可能的。为了证明这一结果，我们采用了可以诱导成年小鼠 Pten 缺失的模型。数据导致了当前的假设，即 PTEN 通过 p16 和细胞周期蛋白 D 调节 b 细胞的再生。为了检验这一假设，我们计划了三个具体目标：首先，我们将研究有丝分裂活性是否在 ¿ - PTEN 缺失诱导的细胞取决于 p16 和细胞周期蛋白 D。其次，我们将确定 PTEN 缺失是否能够诱导 ¿ -超过年龄（1岁）的小鼠细胞，生理刺激不再能增强 ¿第三，我们将确定 PTEN 是否通过 PI3K/AKT 信号传导调节 p16。该分析的结果将大大提高对如何调节 p16 的理解。 -细胞再生并揭示需要操纵哪些分子来促进其再生。