Physiological regulation and function of asymmetric stem cell division

干细胞持续产生高度分化但寿命短的细胞，如 作为血液、皮肤、肠道上皮和精子细胞贯穿整个生命。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， 在维持组织动态平衡方面起着至关重要的作用。这项研究提案的目的是 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的不对称干细胞分裂的调节 克隆干细胞(GSCs)作为模型系统。我们之前已经证明了中心体 GSC内相对于生态位的定向在不对称GSC中起着核心作用 组织。我们的初步结果表明，存在一个检查点机制 监测GSC内正确的中心体方向，确保结果不对称 干细胞分裂的可能性。我们将描述这一检查点(称为“定向” Checkpoint“)，并旨在确定检查点机制的组件。我们将 调查检查点在哪个细胞周期阶段阻止/延迟GSC细胞周期 对中心体定位错误的反应。我们还将采取候选方法来 确定方向检查点的组件。此外，我们将调查 这种检查点机制在与年龄相关的组织衰退中的潜在作用 再生能力。我们的目标是了解成体干细胞确保维持 干细胞和分化细胞群体。对这种机制的理解 可能允许我们操纵干细胞的行为；例如，正常的干细胞可以 在培养中扩增用于移植，或者我们可以抑制癌细胞的扩张 干细胞。

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.