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

点击翻译按钮获取中文摘要

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.