Control of Stem Cell Dynamics by a Niche at Steady-State and During Aging

干细胞是组织稳态所必需的，并且通常定位于特定的小生境， 控制其功能。以这种方式，小生境几乎控制了干细胞动力学的所有方面， 干细胞的这些特性对于组织维持是必不可少的。最近的研究表明， 精确的细胞结构是重要的，以使一个小生境与茎忠实地沟通， 它控制的细胞一个主要的问题是，该领域不了解如何利基最初形成的一个 组织，也不是构成干细胞动力学的关键细胞生物学步骤。我发现这正是 由生态位信号调节。在过去的五年里，我们的实验室在这些问题上取得了重大进展 多年的GM融资。 首先，在确定了小生境细胞特化的关键信号和转录调节因子后，我们揭示了 生态位形成的动力学。这使我们能够提出潜在的机制， 生态位形态发生对它的功能至关重要。我们在这方面追求潜在的机制， 建议，利用我们对细胞骨架控制细胞-细胞组织的知识， 特别是肌动球蛋白收缩性和RhoA信号传导的参与。 其次，我们发现，生态位对基本的细胞过程施加了精确的控制 例如分裂和中间体遗传，以便在组织分化期间调节干细胞动力学， 体内平衡和压力，如老化。我们发现这两种失调 基本的细胞生物学过程损害组织功能。此外，控制 建议中详细说明的中体继承应该对我们的 了解正常细胞和癌细胞如何处理中心体数量缺陷。 为了解决我们的假设，我们联合收割机结合了强大的遗传和molecalur方法， 使用Drosohila，与细胞力学中最先进的测定，包括高空间和 时间实时成像、FRAP和激光消融。 总的来说，我们的方法应该揭示出正确建立利基的机制， 揭示了干细胞维持组织的重要细胞特征。 !

Stem cells are necessary for tissue homeostasis, and are often localized to specialized niches that control their function. In this manner, niches control virtually all aspects of stem cell dynamics, and these properties of stem cells are essential to tissue maintenance. Recent work has shown that precise cellular architecture is important in order for a niche to communicate with fidelity to the stem cells it controls. A major issue is that the field does not understand how niches are initially formed in a tissue, nor the key cell biological steps that constitute stem cell dynamics., and how these are regulated by niche signals. Our lab made significant advances on these questions over the past five years of GM funding. First, after identifying key signals and transcriptional regulators of niche cell specification, we revealed the dynamics of niche formation by live-imaging. This enabled us to suggest mechanisms underlying niche morphogenesis that are so central to its function. We pursue the underlying mechanisms in this proposal, capitalizing on our knowledge of cytoskeletal control over cell-cell organization, and in particular the involvement of actomyosin contractility and RhoA signaling. Second, we discovered that the niche imposes precise control over fundamental cellular processes such as abscission and midbody inheritance in order to regulate stem cell dynamics during tissue homeostasis and upon stresses, such as aging. We found that dysregulations of either of these fundamental cell biological processes compromises tissue function. Furthermore, the control of midbody inheritance as detailed in the proposal should have an impact generally on our understanding of how normal and cancer cells deal with defects in centrosome number. To address our hyptheses, we combine the powerful genetic and molecalur approaches available in using Drosohila, with state-of-the-art assays in cellualr mechanics, which include high spatial and temporal live-imaging, FRAP and laser ablation. Collectively, our approaches should reveal the undelying mechnics that establish a niche properly, and reveal important cellular features that allow stem cells to maintain tissues. !