Transcriptional regulation of pancreas development and function

描述(申请人提供)：所有形式的糖尿病的共同之处是内分泌胰腺中产生胰岛素的功能性细胞逐渐丧失。了解内分泌胰腺的发育和功能是开发治疗这种疾病的新疗法的基础。遗传学研究表明，转录因子在调节细胞的建立和维持方面起着至关重要的作用。胰岛-1(Islet-1，ISL-1)是一种含有同源结构域的转录因子，在胚胎前部表达，后来在成人胰岛细胞中表达，对内分泌细胞的早期分化是必不可少的。然而，由于ISL-1缺陷小鼠的早期胚胎致死性，ISL-1在调节细胞生长、存活和功能中的作用尚未被阐明。在过去的一年里，我们利用Pdx1-Cre/ISL-1/loxP/loxP小鼠，在理解ISL-1在第二波内分泌细胞分化中的作用方面取得了重大进展。在接下来的五年里，我们计划利用可诱导的小鼠模型来研究ISL-1在更具体的发育阶段中的作用。我们假设ISL-1是出生后细胞生长和/或生存以及功能所必需的，并且是细胞通过直接激活MafA和Insulin转录来调节MafA和Insulin表达所必需的。在目标1和3中，我们将使用可诱导的小鼠模型专门测试ISL-1在新生儿细胞重塑和成年细胞功能过程中的作用。目的2确定ISL-1调控MafA和Insulin基因表达的分子机制。这些数据将加深我们对细胞生物学的理解，并可能导致治疗糖尿病的新疗法。与公共卫生相关：糖尿病是一种代谢紊乱，目前影响全球超过1.8亿人。更换丢失的或功能不正常的部件 ？-细胞是治愈、治疗或预防糖尿病的最好的可能性。本申请中描述的实验将有助于描述控制细胞生长和发育的机制，并使我们更接近于为细胞替代疗法创造功能细胞。

DESCRIPTION (provided by applicant): Common to all forms of diabetes is the gradual loss of functional insulin-producing ¿-cells in the endocrine pancreas. Understanding the development and function of the endocrine pancreas is fundamental to the development of novel therapeutics for this disease. Genetic studies have revealed that transcription factors play an essential role in regulating the establishment and maintenance of ¿-cells. Islet-1 (Isl-1), a homeo- domain containing transcription factor expressed in embryonic foregut and later in adult islet cells, is essential for early endocrine cell differentiation. However, because of the early embryonic lethality of Isl-1 deficient mice, the roles of Isl-1 in the regulation of ¿-cell growth, survival and function have not been addressed. In the past year, we have made significant progress to our understanding of the role of Isl-1 during second wave of endocrine cell differentiation using the Pdx1-Cre/Isl-1/LoxP/LoxP mice. Over the next five years we plan to investigate the role of Isl-1 at more specific developmental stages utilizing an inducible mouse model. We hypothesize that Isl-1 is required for postnatal ¿-cell growth and/or survival as well as function and is required in ¿-cells to regulate MafA and Insulin expression through direct activation of MafA and Insulin transcription. In Aim 1 and 3, we will specifically test the role of Isl-1 during neonatal ¿-cell remodeling and during adult ¿-cell function using an inducible mouse model. Aim 2 will determine the molecular mechanism by which Isl-1 regulates MafA and Insulin gene expression. These data will further our understanding of ¿-cell biology and may lead to novel therapeutics for the treatment of diabetes mellitus. PUBLIC HEALTH RELEVANCE: Diabetes mellitus is a metabolic disorder that currently affects over 180 million people worldwide. Replacement of lost or improperly functioning ¿-cells represents the best possibility to cure, treat, or prevent diabetes. The experiments described in this application will help delineate the mechanisms controlling the growth and development of ¿-cells and bring us closer to generating functional ¿-cells for cell replacement therapy.