Control of reproductive aging by germline stem cells

生殖干细胞控制生殖衰老

• 批准号: 10751240
• 负责人: Aaron Marcus Anderson
• 金额: $ 3.36万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751240
• 关键词: Address; Adult; Afferent Neurons; Age; Aging; Alleles; Animals; Binding; Binding Sites; Caenorhabditis elegans; Cell Maintenance; Cells; Development; Dexamethasone; Distal; Ectopic Expression; Epitopes; Event; Evolution; Failure; Foundations; Gene Expression; Genes; Genetic; Goals; Gonadal structure; Health; Human; Intervention; Knowledge; Ligands; Logic; Longevity; Mammals; Mediating; Meiosis; Methods; Modeling; Molecular; Monitor; Neurons; Notch Signaling Pathway; Pathway interactions; Physiology; Process; Production; Public Health; Reagent; Regulation; Rejuvenation; Reporting; Reproduction; Research; Scientist; Signal Transduction; Stem Cell Development; Structure; System; Testing; Tissues; Training; Transforming Growth Factor beta; adult stem cell; age related; egg; exhaustion; experimental study; gain of function; germline stem cells; glucagon-like peptide 1; granulysin; healthspan; healthy aging; improved; in vivo; innovation; juvenile animal; mature animal; model organism; neurotransmission; notch protein; novel strategies; precursor cell; preservation; progenitor; promoter; protein expression; receptor function; reproductive senescence; skills; sperm cell; stem cell aging; stem cell biology; stem cell function; stem cell niche; stem cell self renewal; stem cells; tissue degeneration; tissue repair; tool; transcription factor

Project Summary/Abstract Adult stem cell exhaustion is a hallmark of aging. However, mechanisms of stem cell exhaustion during aging are largely unknown, and there are no therapies that can delay stem cell aging in humans. C. elegans is a premier model organism for studying aging; adult animals are short lived and only contain one stem cell pool, the germline stem cells that generate eggs and sperm. Extensive developmental studies have provided a rich description of the molecular and cellular events that control these stem cells in young animals. My goal is to understand stem cell exhaustion, and my strategy is to exploit the experimental power of C. elegans and the detailed knowledge of stem cell development to elucidate stem cell aging. The somatic distal tip cell (DTC) serves as the stem cell niche by expressing the Notch pathway ligands LAG-2 and APX-1, which bind and activate the GLP-1/Notch receptor in the stem cells. Notch signaling pathways are conserved during evolution and have been repeatedly implicated in regulating stem cells in mammals, suggesting the niche/stem cell system in worms is likely to be broadly relevant. Elucidating the regulatory logic of this system will advance the fields of reproductive aging and stem cell exhaustion. Preliminary results from our lab demonstrate that the number and activity of germline stem cells decline rapidly and progressively with age. Based on these results, I propose two innovative hypotheses. (1) An age-related decline in Notch signaling from the DTC niche causes stem cell exhaustion. (2) Neuronal TGF-β signaling mediates the activity of the DTC niche and contributes to the age- related decline of adult stem cells in the germline. To test these hypotheses, I propose two specific aims. Aim 1: Elucidate mechanisms of Notch pathway regulation during adult stem cell aging in the germline. I will monitor LAG-2 ligand expression in the DTC niche during aging and analyze LAG-2 ligand and Notch receptor function. The results will rigorously test my hypothesis by establishing how LAG-2 ligand expression is regulated during aging and whether LAG-2 ligand and/or GLP-1/Notch receptor are sufficient to sustain stem cell activity during aging. Aim 2: Determine how sensory neurons regulate the DTC niche to mediate germline stem cell aging. I will analyze the DAF-3 binding site in the lag-2 promoter, and the DAF-3 and DAF-5 transcription factors that are the effectors of TGF-β signaling. I will examine multiple levels of organization including protein expression, stem cell dynamics, and progeny production. The results will establish how neuronal signals control the niche and stem cells during aging. The mechanisms of stem cell exhaustion remain mysterious, and these experiments will advance the field by determining the contributions of neurons, the niche, and the stem cells themselves. The results will establish a foundation of knowledge that may stimulate innovative approaches to preserve stem cell function and promote healthy aging in humans.

项目摘要/摘要 成人干细胞衰竭是衰老的一个标志。然而，衰老过程中干细胞耗竭的机制 在很大程度上是未知的，也没有治疗方法可以延缓人类干细胞的衰老。线虫是一种 研究衰老的主要模式生物；成年动物寿命短，只有一个干细胞池， 产生卵子和精子的生殖系干细胞。广泛的发展研究提供了丰富的 描述在幼年动物体内控制这些干细胞的分子和细胞事件。我的目标是 了解干细胞枯竭，我的策略是利用线虫和 干细胞发育的详细知识，以阐明干细胞的老化。体细胞远端顶端细胞(DTC) 通过表达Notch通路配体LAG-2和APX-1作为干细胞利基，它们结合并激活 干细胞中的GLP-1/Notch受体。Notch信号通路在进化过程中是保守的，并且 反复涉及调控哺乳动物的干细胞，表明蠕虫中的利基/干细胞系统是 可能具有广泛的关联性。阐明这一制度的监管逻辑将推动 生殖老化和干细胞衰竭。我们实验室的初步结果表明， 随着年龄的增长，生殖系干细胞的活性迅速递减。基于这些结果，我建议 两个创新的假设。(1)来自DTC小生境的Notch信号与年龄相关的下降导致干细胞 疲惫不堪。(2)神经元性转化生长因子-β信号介导DTC-Nache的活动，并参与年龄- 生殖系中成体干细胞的相关衰退。为了检验这些假设，我提出了两个具体目标。目标 1.阐明生殖系成体干细胞老化过程中Notch通路的调控机制。这就做 监测衰老过程中DTC壁龛中LAG-2配体的表达，分析LAG-2配体和Notch受体 功能。这些结果将通过确定LAG-2配体的表达是如何调控的来严格检验我的假设 在衰老过程中以及Lag-2配体和/或GLP-1/Notch受体是否足以维持干细胞的活性 在衰老过程中。目的2：确定感觉神经元如何调节DTC小生境以介导生殖系干细胞 细胞老化。我将分析LAG-2启动子中的DAF-3结合部位，以及DAF-3和DAF-5的转录 影响转化生长因子-β信号转导的因素。我将研究包括蛋白质在内的多个层次的组织 表达、干细胞动力学和后代生产。研究结果将确定神经元信号如何控制 老化过程中的壁龛和干细胞。干细胞耗尽的机制仍然是个谜，这些 实验将通过确定神经元、壁龛和干细胞的贡献来推进这一领域 他们自己。结果将建立一个知识基础，可能会激励创新的方法 保护干细胞功能，促进人类健康衰老。