Polycomb genes regulation of beta cell regeneration

多梳基因调控β细胞再生

• 批准号: 8967681
• 负责人: Anil Bhushan
• 金额: $ 35.79万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8967681
• 关键词: Polycomb; genes; regulation; beta; cell

DESCRIPTION (provided by applicant): Understanding the molecular mechanisms that regulate beta cell mass have important ramification for fostering beta cell regeneration and the treatment of diabetes. We present data to show that the ability to expand beta cell mass declines with age and is correlated with reduced beta cell replication. We have begun to elucidate the molecular mechanisms responsible for age-dependent decline in the regenerative capacity of beta cells. In preliminary data we show that the Polycomb group genes Bmi-1 regulate the Ink4/Arf locus to limit the proliferative capacity of beta cells. Mice that lack Bmi-1 display diminished beta cell mass, hypoinsulinaemia and glucose intolerance due to premature senescence limiting the expansion of beta cell mass. Although decline in the capacity of beta cell to expand can be correlated with beta cell replication, we will assess which cellular compartment Bmi-1 acts to regulate beta cell mass expansion. We hypothesize that controlled targeting of Bmi-1 pathway could rejuvenate beta cells by extending their regenerative capacity. This enhancement in regenerative capacity could be harnessed to promote beta cell regeneration and expansion of beta cell mass in diabetic mouse models. We propose to investigate the role of age-dependent decline in beta cell replication in regulating beta cell expansion, mechanism by which Bmi-1 and other polycomb group proteins repress the Ink4/Arf locus and regulate beta cell replication and establish whether the Bmi-1 pathway can be targeted in cell-based therapies. Such an approach that exploits the mechanisms involved in the expansion of beta cell mass due to physiologic demands will be critical in developing novel therapeutic approaches that involve beta-cell regeneration in diabetic patients.

描述（由申请人提供）：了解调节β细胞量的分子机制具有促进β细胞再生和糖尿病治疗的重要影响。我们提供数据，以表明扩展β细胞质量随着年龄的增长而下降，并且与β细胞复制减少相关。我们已经开始阐明β细胞再生能力年龄依赖性下降的分子机制。在初步数据中，我们表明Polycomb基因BMI-1调节Ink4/ARF基因座以限制β细胞的增殖能力。缺乏BMI-1显示的小鼠由于过早的衰老限制了β细胞质量的扩展，因此β细胞肿块，低毒性血症和葡萄糖不耐症减少。尽管β细胞扩展的能力下降可能与β细胞的复制相关，但我们将评估哪些细胞室BMI-1 ACT的作用以调节β细胞质量膨胀。我们假设BMI-1途径的受控靶向可以通过扩展其再生能力来恢复β细胞。可以利用这种增长能力的增强能力来促进糖尿病小鼠模型中β细胞量的β细胞再生和扩展。我们建议研究年龄依赖性下降在β细胞复制中的作用在调节β细胞扩展中的作用，BMI-1和其他PolyComb组蛋白抑制INK4/ARF基因座并调节β细胞的复制并确定BMI-1途径是否可以在基于细胞的治疗中靶向BMI-1途径。这种方法利用由于生理需求而导致的β细胞质量扩展的机制对于开发涉及糖尿病患者β细胞再生的新型治疗方法至关重要。