Stem cell aging and the control of abscission

干细胞衰老和脱落的控制

• 批准号: 8891706
• 负责人: STEPHEN Francis DINARDO
• 金额: $ 20万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8891706
• 关键词: Ablation; Accounting; Actins; Adhesions; Affect; Age; Aging; Behavior; Cell Aging; Cell Cycle; Cell Cycle Regulation; Cell Lineage; Cell physiology; Cells; Centrosome; Cultured Cells; Cyclin B; Cyst; Cytokinesis; Cytoskeleton; Data; Development; Dominant-Negative Mutation; Dose; Drosophila genus; Event; Excision; Exercise; F-Actin; Genetic; Homeostasis; Image; Lasers; Life; Link; Mechanics; Mesenchymal Stem Cells; Microfilaments; Microtubules; Myosin Type II; Organ; Phase; Play; Process; Production; Regulation; Rho-associated kinase; Role; Seminal; Signal Transduction; Staging; Stem cells; Structure; System; Testing; Testis; Time; Tissues; Variant; Work; adult stem cell; age related; aurora B kinase; base; cell age; cofilin; daughter cell; dosage; germline stem cells; in vivo; inhibitor/antagonist; novel; public health relevance; response; stem cell division; stem cell niche; stem cell population; trafficking

 DESCRIPTION (provided by applicant): Our tissues inexorably decline during aging. A cause of this is intrinsic changes to the stem cells responsible for tissue homeostasis, or changes in the niche regulating stem cell activity. To explore potential links between cytoskeletal function and aging, there can be great advantage to studying a tissue that has already contributed fundamentally to our understanding of the impact of aging on stem cell function. The Drosophila testis is such a tissue, as germline stem cells (GSCs) have been shown to age, and both intrinsic and extrinsic regulators have been defined. To maintain tissue homeostasis, stem cells must exercise tight spatial and temporal control over daughter cell production. Thus, we have focused on abscission, the last step of cytokinesis, involving the complete separation of daughter cells. Abscission is a key point of regulation generally during cytokinesis, and microtubule and f-actin cytoskeletal dynamics play seminal roles during this process. Abscission has been difficult to image in vivo, but we have been successful using simultaneous imaging of Actin and Myosin II. Our analysis shows that abscission is dramatically delayed in GSCs, even after the contractile ring and the midbody microtubules are disassembled. Surprisingly, a new, filamentous actin-enriched structure succeeds the contractile ring, and serves to stabilize the midbody. We define a regulatory circuit controlling this novel cytoskeletal feature, as well as controls by Aurora B Kinase. Lastly, we find that aging significantly affects abscission, opening up this system to the study of aging and the cytoskeleton. Due to the ease of genetic and pharmacological manipulations, along with the well-characterized behavior of GSCs at steady state and upon aging, the Drosophila testis provides an ideal system in which to study the temporal dynamics, genetic control and roles for cytoskeletal components in abscission events. Here, we test for potential causative links between cytoskeletal control over abscission and aging within this adult stem cell population.

 描述（由申请人提供）：我们的组织在衰老过程中不可避免地衰退。其原因是负责组织稳态的干细胞发生内在变化，或者调节干细胞活性的生态位发生变化。为了探索细胞骨架功能与衰老之间的潜在联系，研究已经为我们理解衰老对干细胞功能的影响做出了根本贡献的组织可能具有很大的优势。果蝇睾丸就是这样一种组织，因为生殖干细胞（GSC）已被证明会老化，并且内部和外部调节因子都已被定义。为了维持组织稳态，干细胞必须对子细胞的产生进行严格的空间和时间控制。因此，我们重点关注脱落，即胞质分裂的最后一步，涉及子细胞的完全分离。脱落是胞质分裂过程中的一个关键调节点，微管和 f-肌动蛋白细胞骨架动力学在此过程中发挥着重要作用。脱落很难在体内成像，但我们已经成功地使用肌动蛋白和肌球蛋白 II 的同步成像。我们的分析表明，即使在收缩环和中体微管被拆卸之后，GSC 的脱落也会显着延迟。令人惊讶的是，一种新的、富含丝状肌动蛋白的结构接续了收缩环，并起到稳定中体的作用。我们定义了一个控制这种新的细胞骨架特征的调节电路，以及 Aurora B 激酶的控制。最后，我们发现衰老显着影响脱落，为衰老和细胞骨架的研究开辟了该系统。由于遗传和药理学操作的简便性，以及 GSC 在稳态和衰老时的良好特征行为，果蝇睾丸提供了一个理想的系统，用于研究时间动态、遗传控制和细胞骨架成分在脱落事件中的作用。在这里，我们测试了成体干细胞群中细胞骨架对脱落的控制与衰老之间的潜在因果关系。