Stem cell aging and the control of abscission

干细胞衰老和脱落的控制

• 批准号: 9144296
• 负责人: STEPHEN Francis DINARDO
• 金额: $ 24万
• 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/9144296
• 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; Health; 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; 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(申请人提供)：我们的组织在衰老过程中会不可避免地衰退。造成这种情况的一个原因是负责组织动态平衡的干细胞的内在变化，或者是调节干细胞活动的利基的变化。为了探索细胞骨架功能和衰老之间的潜在联系，研究一个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会有很大的好处。果蝇的睾丸是这样的组织，因为生殖系干细胞(GSCs)已经被证明是衰老的，内在和外在调节因素都已经被定义。为了维持组织内环境的稳定，干细胞必须对子代细胞的产生进行严格的时空控制。因此，我们将重点放在胞质分裂的最后一步--脱落，这涉及到子细胞的完全分离。在细胞质分裂过程中，脱落通常是一个关键的调节点，而微管和f-肌动蛋白细胞骨架动力学在这一过程中起着至关重要的作用。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同时成像。我们的分析表明，GSCs的脱落显著延迟，即使在收缩环和中体微管解体后也是如此。令人惊讶的是，在收缩环之后，一个新的丝状肌动蛋白丰富的结构，起到稳定中体的作用。我们定义了一个控制这个新的细胞骨架特征的调节电路，以及由Aurora B Kinase控制的调节电路。最后，我们发现衰老对脱落有显著的影响，这为衰老和细胞骨架的研究开辟了新的途径。由于遗传和药物操作的简便性，以及GSCs在稳定状态和衰老时的良好特性，果蝇睾丸为研究时间动力学、遗传控制和细胞骨架组件在脱落事件中的作用提供了一个理想的系统。在这里，我们在成年干细胞群体中测试细胞骨架对脱落的控制和衰老之间的潜在致病联系。