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

描述(申请人提供)：了解调节β细胞质量的分子机制对于促进β细胞再生和糖尿病的治疗具有重要的分支作用。我们提出的数据表明，扩大β细胞质量的能力随着年龄的增长而下降，并与β细胞复制减少有关。我们已经开始阐明与年龄相关的β细胞再生能力下降的分子机制。在初步数据中，我们发现Polycomb组基因Bmi-1调节INK4/Arf位点以限制β细胞的增殖能力。缺乏BMI-1的小鼠表现出由于过早衰老限制了β细胞团的扩张而导致的β细胞团减少、低胰岛素血症和葡萄糖耐量减低。虽然β细胞扩增能力的下降可能与贝塔细胞的复制有关，但我们将评估BMI-1在调节贝塔细胞质量扩张方面的作用。我们假设，通过控制BMI-1通路的靶向，可以通过延长β细胞的再生能力来恢复其活力。这种再生能力的增强可以被用来促进糖尿病小鼠模型中β细胞的再生和β细胞团的扩张。我们建议研究年龄依赖性的β细胞复制下降在调节β细胞扩张中的作用，Bmi-1和其他多聚组蛋白抑制INK4/Arf基因位点和调节β细胞复制的机制，并确定Bmi-1通路是否可以作为细胞治疗的靶点。这种方法利用了由于生理需求而导致的β细胞团扩张的机制，对于开发涉及糖尿病患者β细胞再生的新治疗方法至关重要。

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.