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Physiological regulation and function of asymmetric stem cell division

干细胞不对称分裂的生理调节和功能

基本信息

批准号：
8390484
负责人：
Yukiko Yamashita
金额：
$ 27.76万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-12-01 至 2013-11-30
项目状态：
已结题

项目摘要

Stem cells continuously produce highly differentiated but short-lived cells, such as blood, skin, intestinal epithelium, and sperm cells throughout life. Asymmetric stem cell division, which produces one self-renewed stem cell and one differentiated cell, plays a critical role in maintaining tissue homeostasis. The aim of this research proposal is to investigate the molecular and cellular mechanisms that govern stem cell behavior, in particular, the regulation of asymmetric stem cell division, using Drosophila male germ line stem cells (GSCs) as a model system. We have previously shown that centrosome orientation within GSCs with respect to the niche plays a central role in asymmetric GSC division. Our preliminary results suggest the existence of a checkpoint mechanism that monitors correct centrosome orientation within GSCs, ensuring an asymmetric outcome of stem cell division. We will characterize this checkpoint (referred to as the "orientation checkpoint") and aim to identify the components of the checkpoint mechanism. We will investigate at which cell cycle stage the checkpoint arrests/delays the GSC cell cycle in response to centrosome misorientation. We will also take a candidate approach to identify the components of the orientation checkpoint. Furthermore, we will investigate the potential role of this checkpoint mechanism in the age-related decline in tissue regenerative capacity. We aim to understand the mechanisms by which adult stem cells ensure to maintain both stem cell and differentiated cell populations. Understanding of such mechanisms may allow us to manipulate stem cell behavior; for example, normal stem cells can be expanded in culture for transplantation, or we can inhibit the expansion of cancerous stem cells.

干细胞持续产生高度分化但寿命短的细胞，例如如血液、皮肤、肠上皮和精子细胞。不对称茎细胞分裂，产生一个自我更新的干细胞和一个分化的细胞，在维持组织内环境稳定方面起着关键作用。本研究提案的目的是是研究控制干细胞行为的分子和细胞机制，特别是利用果蝇雄性生殖细胞调节干细胞的不对称分裂系干细胞（GSC）作为模型系统。我们之前已经证明中心体相对于生态位的GSC内的取向在不对称GSC中起着核心作用师.我们的初步结果表明存在一个检查点机制，监测GSC内中心体的正确方向，确保不对称结果干细胞分裂的过程。我们将描述这个检查点（称为“方向检查点”），并旨在确定检查点机制的组成部分。我们将研究检查点在哪个细胞周期阶段阻止/延迟GSC细胞周期，对中心体错误定位的反应。我们还将采取候选方法，识别定向检查点的组件。此外，我们将调查这种检查点机制在组织衰老相关性衰退中的潜在作用再生能力我们的目标是了解成体干细胞确保维持干细胞和分化的细胞群体。了解这些机制可以让我们操纵干细胞的行为;例如，正常的干细胞可以或者我们可以抑制癌细胞的扩散，干细胞