Epigenetic and Genetic Control of Human and Murine Beta Cell Development and Fate

描述(由申请人提供)：根据Beta细胞生物学联盟(BCBC)的研究重点，我们组建了一个由知名研究人员组成的强大的多学科团队，以确定人类胰腺(细胞)发育、生长、成熟、功能和命运控制的表观遗传和遗传程序。人类胰腺和胰岛发育生物学知识的增长将加速糖尿病细胞疗法的创建，我们在此建议进行以胎儿、青少年和成人(-细胞)为实验重点的研究。在这些研究中，我们的团队创造并分享了新的试剂和实验方法，包括人类和小鼠的遗传工具，人类胰岛的采购和持续的生理(细胞)增殖，细胞纯化策略，以及基因组规模的分子图谱。我们将利用这些和其他创新资源来研究产生功能性(-细胞)的有前景的机制，包括从多潜能人类干细胞衍生、细胞重新编程和现有(-细胞)的扩增。在项目1中，我们将结合先进的小鼠遗传学、细胞纯化和基因组学来阐明控制胰岛细胞和其他胰腺细胞亚群的发育和命运的遗传和表观遗传机制。这些研究应该为指导受控细胞重编程再生(-细胞)奠定遗传学和表观遗传学基础。在项目2中，我们将通过从胎儿和幼年人胰腺中提纯特定的细胞亚群，并应用基因表达和染色质的超高通量基因组规模研究，来研究人类胰腺和胰岛细胞发育和成熟的遗传和表观遗传学基础。在项目3中，我们将创建新的人类诱导多能干细胞(IPS)细胞系，这些细胞系携带编码胰腺细胞发育、成熟和功能关键调节因子的基因突变。这些iPS细胞系将提供一个独特的实验平台，以揭示控制人类胰岛细胞发育、命运和功能的基本遗传和表观遗传机制。通过我们的研究在BCBC中促进的数据共享、假设和合作应该会加速实现BCBC发现糖尿病细胞疗法的任务的进展。 公共卫生相关性：为了与Beta细胞生物学联盟所述的优先事项保持一致，我们的研究团队建议确定人类胰岛发育、生长、成熟和功能的分子程序，以加快糖尿病细胞疗法的进展。我们将研究有前景的产生功能性β细胞的机制，包括从多潜能人类干细胞衍生，其他胰腺细胞的重新编程，以及现有的β细胞的扩增。

DESCRIPTION (provided by applicant): In alignment with Beta Cell Biology Consortium (BCBC) research priorities, we have assembled a strong multidisciplinary team of established investigators to identify epigenetic and genetic programs underlying human pancreatic (-cell development, growth, maturation, function, and fate control. Growth of knowledge about human pancreas and islet developmental biology will accelerate creation of cell therapies for diabetes mellitus, and we propose studies here with an experimental focus on fetal, juvenile and adult human (-cells. For these studies, our team has created and shared new reagents and experimental methods, including human and mouse genetic tools, procurement of human islets with ongoing physiological (-cell proliferation, cell purification strategies, and genome-scale molecular profiling. We will use these and other innovative resources to investigate promising mechanisms for generating functional (-cells, including derivation from multipotent human stem cells, cell reprogramming, and expansion of existing (-cells. In Project 1, we will combine the power of advanced mouse genetics, cell purification, and genomics to elucidate genetic and epigenetic mechanisms controlling development and fates of islet (-cells and other pancreatic cell subsets. These studies should establish genetic and epigenetic foundations for directing controlled cell reprogramming to regenerate (-cells. In Project 2, we will investigate the genetic and epigenetic basis for human pancreatic and islet cell development and maturation, by purifying defined cell subsets from fetal and juvenile human pancreata and applying 'ultrahigh' throughput genomic-scale studies of gene expression and chromatin. In Project 3, we will create new human induced pluripotent stem (iPS) cell lines harboring mutations in genes encoding crucial regulators of pancreatic (-cell development, maturation, and function. These iPS cell lines will provide a unique experimental platform to reveal fundamental genetic and epigenetic mechanisms controlling human islet (-cell development, fate and function. Data sharing, hypotheses, and collaborations fostered in the BCBC through our studies should speed progress toward meeting the BCBC mandate to discover cellular therapies for diabetes mellitus. PUBLIC HEALTH RELEVANCE: In alignment with stated Beta Cell Biology Consortium priorities, our team of investigators proposes to identify the molecular programs underlying human pancreatic islet development, growth, maturation and function to accelerate progress toward cell therapies for diabetes mellitus. We will investigate promising mechanisms for generating functional beta cells, including derivation from multipotent human stem cells, reprogramming of other pancreatic cells, and expansion of existing beta cells.