Physiological regulation and function of asymmetric stem cell division

描述（由申请人提供）：干细胞在一生中持续产生高度分化但寿命短的细胞，如血液、皮肤、肠上皮和精子细胞。不对称干细胞分裂产生一个自我更新的干细胞和一个分化的细胞，在维持组织稳态中起着关键作用。本研究拟以果蝇雄性生殖系干细胞（GSCs）为模型系统，探讨控制干细胞行为的分子和细胞机制，特别是干细胞不对称分裂的调控。我们之前已经证明，相对于生态位，GSC内中心体的取向在GSC不对称分裂中起着核心作用。我们的初步结果表明，存在一种检查点机制，可以监测gsc内中心体的正确方向，确保干细胞分裂的不对称结果。我们将描述这个检查点（称为“定向检查点”），并旨在确定检查点机制的组件。我们将研究在哪个细胞周期阶段，检查点阻止/延迟GSC细胞周期以响应中心体定向错误。我们还将采用一种候选方法来标识方向检查点的组件。此外，我们将研究这种检查点机制在与年龄相关的组织再生能力下降中的潜在作用。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.