The mechanism of beta-cell regeneration

β细胞再生机制

• 批准号: 8269893
• 负责人: Bangyan Stiles
• 金额: $ 28.07万
• 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/8269893
• 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. 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.

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。 公共健康相关性：糖尿病是由胰腺中 β 细胞的丢失或退化引起的。通常，成人中 β 细胞的替换非常缓慢。该提案的目的是找出加速 β 细胞替换的方法。以达到治愈糖尿病的目的。