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（由适用提供）：我们在衰老期间无可避免地下降。原因是负责组织稳态的干细胞的内在变化，或者是小众调节干细胞活性的变化。为了探索细胞骨架功能与衰老之间的潜在联系，研究已经对我们对衰老对干细胞功能的影响的理解做出贡献的组织可能会有很大的优势。果蝇睾丸是这样的组织，因为已经显示出生殖线干细胞（GSC）的年龄，并且已经定义了内在的和外在的调节剂。为了维持组织稳态，干细胞必须对女儿细胞产生进行严格的空间和暂时控制。因此，我们专注于脱落，这是细胞因子的最后一步，涉及子细胞的完全分离。脱落是在细胞球运动过程中通常的关键调节点，在此过程中，微管和F-肌动蛋白细胞骨架动力学起着第二作用。脱落很难在体内图像，但是我们已经成功地使用了肌动蛋白和肌球蛋白II的简单成像。我们的分析表明，即使在收缩环和中体微管被拆卸后，GSC的脱落也会大大延迟。令人惊讶的是，一种新的丝状肌动蛋白含有的结构成功了收缩环，并为我们定义了控制这一新型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，使该系统对衰老和细胞骨架的研究开放。由于遗传和药物操纵的易于性，以及在稳态和衰老时GSC的特征良好的行为，果蝇睾丸提供了一个理想的系统，可以在其中研究临时动力学，遗传控制和在脱落事件中细胞骨架成分的作用。在这里，我们测试了该成年干细胞种群中对脱落的细胞骨架控制与衰老之间的潜在严重联系。