Molecular Regulation of Pancreas Cell Fate Determination

描述(由申请人提供)： 大多数器官包含各种分化的细胞类型，这些细胞类型来自一群未被定位的祖细胞。如何确定不同细胞类型的正确数量--细胞命运决定的过程--是器官发生学中的一个中心问题。这个问题适用于胰腺，它包含产生消化酶的外分泌细胞和产生包括胰岛素在内的胰腺激素的内分泌细胞。该项目的目标是通过决定细胞命运的过程，了解胰腺前体细胞被指示成为外分泌或内分泌细胞的机制。 先前的工作表明，Notch-一种复杂的受体信号通路，在胚胎发育过程中被广泛用于控制分化-在决定胰腺细胞命运方面发挥着重要作用。这项提案旨在回答三个问题。首先，对Notch信号的操纵能否导致形成的外分泌和内分泌细胞比例的变化？这将通过在转基因小鼠中错误表达Notch途径的激活剂和抑制剂来解决，以确定对细胞命运的影响。第二，胰腺中的Notch信号是如何调节的？当已知的内分泌分化介体在鸡胚胎中表达时，将通过表征Notch途径的元件的表达来解决这一问题。第三，小鼠Sel-1蛋白的功能是什么，它是线虫Notch的负调控因子，在哺乳动物的胰腺中表达。这将通过使Sel-1基因失活来解决。 阐明胰腺中细胞命运决定的机制将增强对器官发生过程的总体理解。许多退行性疾病，包括胰腺功能不全和I型糖尿病，都是由于失去了重要的分化细胞类型。实际上，对生物体指定这种细胞类型的机制的了解可能会赋予实验操作组织进行治疗的能力。

DESCRIPTION (provided by applicant): Most organs contain a variety differentiated cell types that are derived from a pool of uncommitted progenitor cells. How the correct number of different cell types are specified - the process of cell fate determination - is a central question in organogenesis. This problem applies to the pancreas, which contains exocrine cells, which produce digestive enzymes, and endocrine cells, which make pancreatic hormones, including insulin. The goal of this project is to understand the mechanism by which pancreatic progenitor cells are instructed to become exocrine or endocrine cells, through the process of cell fate determination. Previous work has suggested that Notch - a complex receptor signaling pathway that is widely used during embryogenesis to control differentiation - plays an important role determining pancreatic cell fate. This proposal aims to answer three questions. First, can manipulation of the Notch signal lead to changes in the proportion of exocrine and endocrine cells that form? This will be addressed by mis-expressing activators and inhibitors of the Notch pathway in transgenic mice to determine the effect on cell fate. Second, how are Notch signals regulated in the pancreas? This will be addressed by characterizing the expression of elements of the Notch pathway when known mediators of endocrine differentiation are expressed in chick embryos. Third, what is the function of the mouse Sel-1l protein, a negative regulator of Notch in C. elegans which is expressed in the mammalian pancreas. This will be addressed by inactivating the Sel-1l gene. Clarifying the mechanism by which cell fate decisions are made in the pancreas will enhance the general understanding of the process of organogenesis. Many degenerative diseases, including pancreatic insufficiency and type I diabetes, result from the loss important differentiated cell types. Practically, an understanding of the mechanisms by which the organism specifies such cell types may confer the ability to experimentally manipulate tissues for therapy.