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

多梳族基因Bmi-1在β细胞再生和衰老中的作用

• 批准号: 8012384
• 负责人: Anil Bhushan
• 金额: $ 9.85万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2010-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8012384
• 关键词: Address; Adult; Age; Aging; Animals; Beta Cell; Cell Proliferation; Cell Therapy; Cells; Control Locus; Data; Diabetes Mellitus; Diabetic mouse; Doxycycline; Engraftment; Exocrine pancreas; Fostering; Genes; Glucose Intolerance; In Vitro; Insulin; Islets of Langerhans; Islets of Langerhans Transplantation; Kidney; Knockout Mice; Life; Light; Link; Metabolic; Modeling; Molecular; Molecular Target; Mus; Natural regeneration; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Physiological; Polycomb; Population; Production; Proliferating; Proteins; Public Health; Regulation; Relative (related person); Repression; Role; Stem cells; Testing; Transgenic Mice; age related; capsule; cell type; derepression; design; diabetic patient; flexibility; gain of function; genome wide association study; hematopoietic tissue; high risk; islet; medical complication; member; mouse model; novel therapeutic intervention; premature; public health relevance; regenerative; senescence

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.

描述（由申请人提供）：了解调节β细胞质量的分子机制对促进β细胞再生和糖尿病治疗具有重要的分支意义。我们提供的数据表明，扩大β细胞质量的能力随着年龄的增长而下降，并与β细胞复制的减少有关。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β细胞质量减少、低胰岛素血症和葡萄糖耐受不良，这是由于过早衰老限制了β细胞质量的扩大。尽管β细胞增殖能力的下降可能与β细胞复制相关，但我们将评估哪个细胞室Bmi-1调节β细胞质量扩增。我们假设控制Bmi-1通路可以通过延长β细胞的再生能力来恢复β细胞的活力。这种再生能力的增强可用于促进糖尿病小鼠模型中的β细胞再生和β细胞质量的扩大。我们拟研究β细胞复制的年龄依赖性下降在调节β细胞扩增中的作用，Bmi-1和其他多梳蛋白抑制Ink4/Arf位点和调节β细胞复制的机制，并确定Bmi-1通路是否可以靶向细胞治疗。这种方法利用了由于生理需求而导致的β细胞质量扩大的机制，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。公共卫生相关性：由于糖尿病患者需要终身胰岛素治疗，并且有很高的医疗并发症风险，因此迫切需要预防性或根治性治疗。糖尿病是由功能性β细胞数量不足引起的，越来越多的证据表明，β细胞增殖与衰老有关，β细胞增殖是β细胞适应不断变化的代谢需求的主要手段。该建议认为，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，这种利用生理需求导致β细胞团扩增的机制的方法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。