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

• 批准号: 7884905
• 负责人: Yukiko Yamashita
• 金额: $ 26万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-20 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7884905
• 关键词: Accounting; Age; Aging; Behavior; Biological Models; Blood; Cancerous; Cell Count; Cell Cycle; Cell Cycle Arrest; Cell Cycle Stage; Cell physiology; Cells; Centrosome; Characteristics; Data; Daughter; Drosophila genus; Ensure; Equilibrium; Failure; Genes; Germ Lines; Homeostasis; Kinetics; Lead; Life; Link; Mediating; Molecular; Monitor; Mothers; Outcome; Physiological; Play; Population; Process; Regulation; Research; Research Proposals; Role; Skin; Spermatogenesis; Spermatogonia; Stem cells; Testing; Testis; Tissues; Transplantation; adult stem cell; age related; aged; base; cell behavior; intestinal epithelium; male; mutant; novel; public health relevance; regenerative; response; self-renewal; sperm cell; stem cell division; stem cell fate

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.

描述（由申请人提供）：干细胞在整个生命过程中不断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。不对称的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。本研究计划的目的是以果蝇雄性生殖系干细胞（GSC）为模型系统，研究支配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。我们以前已经表明，GSC内的中心体定位相对于生态位在不对称GSC分裂中起着核心作用。我们的初步结果表明，存在一个检查点机制，监测GSC内的正确中心体方向，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“方向检查点”），并旨在确定检查点机制的组成部分。我们将调查在哪个细胞周期阶段的检查点逮捕/延迟GSC细胞周期响应中心体错误定位。我们还将采用候选方法来识别方向检查点的组件。此外，我们还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。 公共卫生关系：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的机制。了解这些机制可能使我们能够操纵干细胞的行为;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性干细胞的扩增。