Effects of aging on stem cell function through systemic signals and mTOR

衰老通过系统信号和 mTOR 对干细胞功能的影响

• 批准号: 8548217
• 负责人: Joseph Thomas Rodgers
• 金额: $ 9.62万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8548217
• 关键词: Ablation; Adult; Age; Aging; Aging-Related Process; Animals; Automobile Driving; Behavioral; Biology of Aging; Blood; Caloric Restriction; Cell Aging; Cell physiology; Cells; Characteristics; Chronic; Complex; Cues; Data; Defect; Development; Diet; Ensure; Environment; Ethical Issues; Exposure to; Faculty; Foundations; Functional disorder; Future; Genetic; Genetic Materials; Genetic Models; Goals; Homeostasis; Hormonal; Hormones; Institutes; Intervention; Knock-out; Lead; Learning; Link; Literature; Longevity; Mediating; Mediator of activation protein; Mentors; Mentorship; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Modeling; Molecular; Muscle; Muscle satellite cell; Nutrient; Organism; Pathology; Pathway interactions; Phosphorylation; Population; Positioning Attribute; Proto-Oncogene Protein c-met; Regulation; Reporting; Research; Research Institute; Research Personnel; Resources; Role; Schools; Science; Serum; Signal Transduction; Stem Cell Research; Stem cells; System; TSC1 gene; Testing; Therapeutic Uses; Tissues; Training; Work; adult stem cell; age effect; age related; aged; base; career; cell age; college; functional decline; human FRAP1 protein; interest; medical schools; meetings; muscle regeneration; neuronal cell body; novel; peptide hormone; prevent; regenerative; response; satellite cell; self-renewal; skills; stem cell biology; tissue regeneration

My driving ambition is to study the relationship between metabolism and aging as an independent investigator. My interest in metabolism started with the metabolic pathways courses I took in college and was cemented in graduate school when I began to study the literature on calorie restriction and life span extension. Learning about calorie restriction made me think about how cells and the body as a whole respond to systemic energy levels. Because of this I decided to concentrate my graduate work at Johns Hopkins School of Medicine on studying how systemic nutrient fluxes are sensed by cells and act in regulation of metabolism. Following this same interest on how cells respond to external signals, I concentrated my postdoctoral work at Harvard Medical School/DFCI on studying the dynamics of hormonal signal transduction. To expand the depth and breadth of my scientific training I have decided to work with Dr. Thomas Rando at Stanford Medical School to gain further expertise in the fields of aging and stem cell biology. Dr. Rando and I share a common view that in many ways aging can be thought of as a systemic condition. Like metabolic diseases, many, if not most aspects of aging may be due to the cellular response to an altered and dysfunctional systemic environment. Understanding the aged systemic environment and how cells respond to this environment will likely yield treatments to ameliorate or prevent many pathologies of aging. Combining my expertise in metabolism and signaling with the skills in aging research and stem cell biology I am developing while working with Dr. Rando puts me in a unique position to be able to study how aging impacts stem cell, tissue, and organismal function in ways that have not been done before. It is well known that with aging there is a decline in tissue homeostasis. The primary function of adult stem cells is to maintain tissue homeostasis by providing the cellular and genetic material that ensures proper tissue function. However, decline in stem cell function with aging is a major contributing factor in age-related tissue dysfunction. Here, we will use adult muscle stem cells (satellite cells) as a model to study how stem cells respond to aging. The foundation of this proposal is based on our observation that satellite cells from aged animals have an aberrant induction of mTORC1 signaling. The mTORC1 signaling complex is a major mediator of the cellular response to external metabolic and hormonal signals and has been widely implicated as a factor in aging and life span. Therefore, we have two major goals in this proposal: 1) to understand the functional role of mTORC1 signaling in satellite cells and 2) to identify the upstream signals which contribute to aberrant mTORC1 activity in satellite cells from aged animals. Using satellite cell specific genetic models to modulate mTORC1 activity our preliminary data show that induction of mTORC1 is sufficient to recapitulate a host of the age-associated satellite cell functional changes: decline in number, loss of self-renewal, and reduced capacity for muscle regeneration. Additionally, we have found that HGF, a serum hormone known to be elevated in aging, is sufficient to induce mTORC1 activity in quiescent satellite cells. These data suggest a model where in aging, systemic factors, HGF, lead to chronic induction of mTORC1 activity in satellite cells which contributes to age related functional decline. In this proposal we will test his model by using genetic and pharmacologic approaches to suppress mTORC1 and HGF signaling in satellite cells to prevent age-related satellite cell dysfunction. The implications ofthis work will be the identification of novel pathways involved in the effects of aging on stem cell function and the molecular mechanisms by which they act, providing a basis for future work in my independent career. Long term goals of this proposal include the therapeutic use of simple dietary or pharmacologic interventions targeting mTORC1 or HGF to correct stem cell dysfunction and ameliorate age related tissue pathologies. The goals of this proposal will be strongly aided by the environment and mentorship provided by Dr. Rando. The Rando lab as part of the Glenn Foundation for Aging Research at Stanford with Drs. Anne Brunet and Steve Artandi cultivate a productive and creative environment for aging and stem cell research. I have enlisted Dr. Brian Kennedy of The Buck Institute for Research on Aging as a co-mentor and Dr. Arvind Ramanathan as a collaborator for their guidance and expertise in the fields of metabolism and TOR signaling as they relate to aging. The work proposed here will give me the resources and opportunity to further develop my research strategy and goals for a smooth transition into an independent career. This will be facilitated by the mentorship of Drs. Rando and Kennedy who will guide me on the logistical, philosophical, and ethical issues of being an independent investigator. Additionally, Drs. Rando and Kennedy will support this transition by using their large network in academic science to help me identify appropriate faculty position openings and will advise me with decisions on how to choose the best institute/environment to start my independent research career.

我的雄心是作为一名独立研究者研究新陈代谢与衰老之间的关系。我对新陈代谢的兴趣始于我在大学学习的代谢途径课程，并在研究生院开始研究有关卡路里限制和延长寿命的文献时得到了巩固。了解卡路里限制让我思考细胞和身体作为一个整体如何对全身能量水平做出反应。因此，我决定将我在约翰霍普金斯大学医学院的研究生工作集中于研究细胞如何感知全身营养通量并在新陈代谢调节中发挥作用。出于对细胞如何响应外部信号的同样兴趣，我在哈佛医学院/DFCI 的博士后工作集中于研究激素信号转导的动力学。为了扩大我的科学培训的深度和广度，我决定与斯坦福大学医学院的 Thomas Rando 博士合作，以获得衰老和干细胞生物学领域的进一步专业知识。兰多博士和我有一个共同的观点，即在很多方面，衰老可以被视为一种全身性疾病。与代谢疾病一样，衰老的许多（如果不是大多数）方面可能是由于细胞对改变的和功能失调的全身环境的反应造成的。了解衰老的全身环境以及细胞如何响应这种环境可能会产生改善或预防许多衰老病理的治疗方法。将我在新陈代谢和信号传导方面的专业知识与我在与 Rando 博士合作期间开发的衰老研究和干细胞生物学技能相结合，使我处于一个独特的位置，能够以前所未有的方式研究衰老如何影响干细胞、组织和有机体功能。众所周知，随着衰老，组织稳态会下降。成体干细胞的主要功能是通过提供确保适当组织功能的细胞和遗传物质来维持组织稳态。然而，干细胞功能随衰老而下降是导致与年龄相关的组织功能障碍的主要因素。在这里，我们将使用成体肌肉干细胞（卫星细胞）作为模型来研究干细胞如何应对衰老。该提议的基础是基于我们的观察，即来自老年动物的卫星细胞对 mTORC1 信号传导有异常诱导。 mTORC1 信号复合物是细胞对外部代谢和激素信号做出反应的主要介质，并被广泛认为是衰老和寿命的一个因素。因此，我们的提案有两个主要目标：1) 了解 mTORC1 信号在卫星细胞中的功能作用，2) 识别导致老年动物卫星细胞中 mTORC1 活性异常的上游信号。使用卫星细胞特异性遗传模型来调节 mTORC1 活性，我们的初步数据表明，mTORC1 的诱导足以重现一系列与年龄相关的卫星细胞功能变化：数量减少、自我更新丧失和肌肉再生能力降低。此外，我们发现 HGF（一种已知在衰老过程中会升高的血清激素）足以诱导静止卫星细胞中的 mTORC1 活性。这些数据表明，在衰老过程中，系统性因素 HGF 会导致卫星细胞中 mTORC1 活性的慢性诱导，从而导致与年龄相关的功能衰退。在本提案中，我们将通过使用遗传和药理学方法抑制卫星细胞中的 mTORC1 和 HGF 信号传导来测试他的模型，以防止与年龄相关的卫星细胞功能障碍。这项工作的意义将是识别衰老对干细胞功能影响的新途径及其作用的分子机制，为我未来的独立职业生涯奠定基础。该提案的长期目标包括针对 mTORC1 或 HGF 的简单饮食或药物干预的治疗用途，以纠正干细胞功能障碍并改善与年龄相关的组织病理学。 Rando 博士提供的环境和指导将有力地帮助实现该提案的目标。兰多实验室是斯坦福大学格伦衰老研究基金会的一部分，与博士一起。 Anne Brunet 和 Steve Artandi 为衰老和干细胞研究营造了一个富有成效和创造性的环境。我聘请了巴克衰老研究所的 Brian Kennedy 博士作为联合导师，Arvind Ramanathan 博士作为合作者，感谢他们在与衰老相关的新陈代谢和 TOR 信号传导领域的指导和专业知识。这里提出的工作将为我提供资源和机会，以进一步制定我的研究策略和目标，以顺利过渡到独立职业生涯。这将在博士的指导下得到促进。兰多和肯尼迪将在作为一名独立调查员的后勤、哲学和道德问题上指导我。此外，博士。兰多和肯尼迪将利用他们在学术科学领域的庞大网络来支持这一转变，帮助我确定合适的教职职位空缺，并就如何选择最好的研究所/环境来开始我的独立研究生涯向我提供建议。