Role of polycomb group gene Bmi-1 in beta cell regeneration and aging

描述（由申请人提供）：了解调节β细胞群的分子机制对于促进β细胞再生和治疗糖尿病具有重要的意义。我们目前的数据表明，扩大β细胞群的能力随着年龄的增长而下降，并与β细胞复制减少有关。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组基因Bmi-1调节Ink 4/Arf位点以限制β细胞的增殖能力。缺乏Bmi-1的小鼠由于过早衰老而表现出β细胞群减少、低胰岛素血症和葡萄糖耐受不良，从而限制了β细胞群的扩增。虽然β细胞扩增能力的下降可能与β细胞复制相关，但我们将评估哪一个细胞区室Bmi-1起调节β细胞群扩增的作用。我们假设Bmi-1通路的受控靶向可以通过延长其再生能力来恢复β细胞。这种再生能力的增强可以用于促进糖尿病小鼠模型中的β细胞再生和β细胞群的扩增。我们建议研究β细胞复制中年龄依赖性下降在调节β细胞扩增中的作用，Bmi-1和其他polycomb组蛋白抑制Ink 4/Arf位点并调节β细胞复制的机制，并确定Bmi-1途径是否可以在基于细胞的治疗中靶向。这种利用由于生理需求而导致的β细胞群扩增所涉及的机制的方法在开发涉及糖尿病患者中的β细胞再生的新型治疗方法中将是至关重要的。公共卫生相关性：由于糖尿病患者需要终身胰岛素治疗并且具有高的医疗并发症风险，因此迫切需要预防性或治愈性治疗。糖尿病是由功能性β细胞质量不足引起的，越来越多的证据表明β细胞增殖（β细胞适应不断变化的代谢需求的主要手段）与衰老有关。该提案认为，了解年龄依赖性β细胞扩增的机制可能对再生β细胞有用，并且利用由于生理需求而导致的β细胞群扩增中所涉及的机制的这种方法在开发涉及糖尿病患者中β细胞再生的新型治疗方法中将是至关重要的。

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. PUBLIC HEALTH RELEVANCE: As diabetic patients require life-long insulin therapy and have a high risk of medical complications, preventative or curative therapies are urgently needed. Diabetes results from an inadequate mass of functional beta cells and there is increasing evidence to suggests that beta cell proliferation, the dominant means by which beta cells adapt to changing metabolic demands, is related to aging. This proposal contends that understanding the mechanisms of age-dependent beta cell expansion could be useful for regenerate beta cells and 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.