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

描述（由申请人提供）：根据β细胞生物学联盟（BCBC）的研究重点，我们组建了一个强大的多学科团队，由成熟的研究人员组成，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学和遗传程序。关于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造，我们在这里提出了以胎儿、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，包括人类和小鼠遗传工具，正在进行的生理细胞增殖的人类胰岛的获取，细胞纯化策略和基因组尺度的分子分析。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希望的机制，包括多能性人类干细胞的衍生、细胞重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的力量来阐明控制胰岛细胞和其他胰腺细胞亚群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以再生细胞建立遗传学和表观遗传学基础。在项目2中，我们将研究人类胰腺和胰岛细胞发育和成熟的遗传和表观遗传基础，从胎儿和青少年胰腺中纯化确定的细胞亚群，并应用基因表达和染色质的“超高”通量基因组尺度研究。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，这些细胞系包含编码胰腺细胞发育、成熟和功能关键调节因子的基因突变。这些iPS细胞系将为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提供一个独特的实验平台。通过我们的研究，在BCBC中促进数据共享、假设和合作，将加速BCBC在发现糖尿病细胞治疗方面的任务。

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.