Molecular Regulation of Pancreas Cell Fate Determination

描述（由申请人提供）： 大多数器官含有多种分化的细胞类型，这些细胞来源于未定型祖细胞库。如何确定不同细胞类型的正确数量-细胞命运决定的过程-是器官发生中的一个中心问题。这个问题也适用于胰腺，胰腺包含产生消化酶的外分泌细胞和产生胰腺激素（包括胰岛素）的内分泌细胞。本项目的目标是了解胰腺祖细胞通过细胞命运决定过程被指示成为外分泌或内分泌细胞的机制。 以前的工作表明，Notch -一种在胚胎发育过程中广泛用于控制分化的复杂受体信号通路-在决定胰腺细胞命运方面起着重要作用。这项建议旨在回答三个问题。首先，Notch信号的调控是否会导致外分泌细胞和内分泌细胞比例的改变？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，Notch信号在胰腺中是如何调节的？这将通过表征当已知的内分泌分化介质在鸡胚中表达时Notch途径的元件的表达来解决。第三，小鼠Sel-1 l蛋白是C.在哺乳动物胰腺中表达。这将通过使Sel-1 l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一般理解。许多退行性疾病，包括胰腺功能不全和I型糖尿病，都是由于重要的分化细胞类型的丢失造成的。实际上，对生物体指定这些细胞类型的机制的理解可以赋予实验性操纵组织用于治疗的能力。

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.