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

我的志向是独立研究新陈代谢与衰老的关系 调查员。我对新陈代谢的兴趣始于我在大学里学的新陈代谢途径课程， 当我开始研究限制卡路里和延长寿命的文献时，我在研究生院得到了巩固。 对卡路里限制的了解让我思考了细胞和身体作为一个整体是如何应对系统性的 能量水平。正因为如此，我决定把我的研究生学业集中在约翰·霍普金斯大学 研究全身营养通量如何被细胞感知并在新陈代谢调节中起作用的医学。 出于对细胞如何响应外部信号的同样兴趣，我将博士后工作集中在 哈佛医学院/DFCI研究荷尔蒙信号转导的动力学。要扩大深度， 在我科学训练的广度上，我决定与斯坦福医学院的托马斯·兰多博士合作 在衰老和干细胞生物学领域获得进一步的专业知识。兰多博士和我有一个共同的观点 在许多方面，衰老可以被认为是一种系统性疾病。就像代谢性疾病一样，即使不是大多数，也有很多 衰老的一些方面可能是由于细胞对改变和功能失调的系统环境的反应。 了解衰老的系统环境和细胞如何对这种环境做出反应可能会产生 治疗以改善或预防许多衰老的病理现象。结合我在新陈代谢方面的专业知识 使用我在与兰多博士合作期间开发的衰老研究和干细胞生物学方面的技能发出信号 使我处于一个独特的位置，能够研究衰老如何影响干细胞、组织和机体功能 以前没有人做过的事情。 众所周知，随着年龄的增长，组织的动态平衡会下降。成体茎的主要功能 细胞是通过提供确保适当组织的细胞和遗传物质来维持组织的动态平衡 功能。然而，随着年龄的增长，干细胞功能的下降是年龄相关组织中的一个主要因素。 功能障碍。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。 这一提议的基础是基于我们的观察，来自老年动物的卫星细胞具有 MTORC1信号的异常诱导。MTORC1信号复合体是细胞内的主要介体。 对外部代谢和激素信号的反应，已被广泛认为是衰老和 寿命。因此，我们在这项提议中有两个主要目标：1)了解mTORC1的功能作用 卫星细胞中的信号和2)识别导致mTORC1活性异常的上游信号 在老年动物的卫星细胞中。利用卫星细胞特异性遗传模型调节mTORC1活性 我们的初步数据显示，mTORC1的诱导足以概括一系列与年龄相关的 卫星细胞功能改变：数量减少，自我更新能力丧失，肌肉能力降低 再生。此外，我们还发现，HGF，一种已知的随着年龄增长而升高的血清激素， 足以在静止的卫星细胞中诱导mTORC1活性。这些数据表明了一个模型，在这个模型中， 系统性因素，HGF，导致卫星细胞mTORC1活性的慢性诱导，这有助于增龄相关 功能衰退。在这个提案中，我们将使用遗传学和药理学来测试这一模型 抑制卫星细胞中mTORC1和HGF信号以防止年龄相关卫星细胞的方法 功能障碍。这项工作的意义将是确定参与影响的新途径 衰老对干细胞功能及其作用的分子机制的影响，为未来的工作提供了基础 在我独立的职业生涯中。这项建议的长期目标包括使用简单的饮食或 针对mTORC1或HGF的药物干预纠正干细胞功能障碍和改善年龄相关性 组织病理学。 这项提议的目标将得到环境和导师的大力帮助。 兰多。作为斯坦福大学格伦老龄化研究基金会的一部分，兰多实验室与安妮·布鲁内特博士一起 史蒂夫·阿坦迪为衰老和干细胞研究创造了一个富有成效和创造性的环境。我有过 聘请了巴克老龄化研究所的布莱恩·肯尼迪博士和阿文德博士作为共同导师 Ramanathan是新陈代谢和TOR信号领域的指导和专业知识的合作者 因为它们与衰老有关。 这里提出的工作将给我进一步发展我的研究的资源和机会 顺利过渡到独立职业生涯的战略和目标。这将得到导师的帮助。 兰多博士和肯尼迪博士将在后勤、哲学和伦理问题上指导我 独立调查员。此外，兰多博士和肯尼迪博士将通过使用他们的大型 帮助我确定合适的教员职位空缺，并将向我提供以下建议 关于如何选择最好的研究所/环境开始我的独立研究生涯的决定。

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 agerelated functional decline. In this proposal we will test this 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 of this 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.