The mechanism of beta-cell regeneration

β细胞再生机制

• 批准号: 8585944
• 负责人: Bangyan Stiles
• 金额: $ 0.15万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 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/8585944
• 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

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）：该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。