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Using Components of the Circadian Clock to Regulate Stem Cell Fate Decisions

利用生物钟的组成部分来调节干细胞的命运决定

基本信息

批准号：
7942482
负责人：
Brian J Feldman
金额：
$ 239.22万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2015-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (Provided by the applicant) Abstract: Tantalizing advances in stem cell biology have led to the promise of incredible new therapeutic options for an array of illnesses. Yet, the reality is that continued obstacles have thus far delayed the translation of most these potential advances in regenerative medicine into the clinic where they can be used for patients. This is in part because of missing tools that control how and when stem cells commit to a lineage (stem cell fate) and differentiate. Glucocorticoids such as cortisol, the natural hormone, or a multitude of synthetic cortisol analogues used as drugs, are heavily relied upon in stem cell biology because of their potent ability to induce cell fate decisions and differentiation of precursor cells. For example, glucocorticoids play a critical role in the induction of adipocyte cell fate and differentiation both in vivo and ex vivo. In fact, glucocorticoids have been indispensable for the progress made in understanding down-stream events of stem cell differentiation. Yet, the mechanisms by which glucocorticoids initiate cell fate decisions is mostly unexplored. Here I propose a novel paradigm where the circadian clock, controlling 24-hour body rhythms, is embedded in the glucocorticoid pathway and is essential for the regulation of stem cell fate. To test my hypothesis, I will develop innovative, interdisciplinary tools to reveal the molecular connections between stem cells, nuclear hormone receptors and circadian rhythm biology. The new knowledge to be gained from these studies will likely allow the design of drugs to direct selective precursor cells down a desirable and healthful lineage of differentiation and away from a disease- oriented path. The potential significance is substantial for both understanding new aspects of stem cell biology and for the development of improved drugs to prevent and/or treat common debilitating diseases such as osteoporosis, degenerative muscle diseases and diabetes. Public Health Relevance: The emergence of the field of stem cell biology has raised the real potential for regenerative medicine to offer treatments and cures for patients suffering from a broad array of illnesses including degenerative muscle diseases, osteoporosis and diabetes. The goal of this project is to test a hypothesis of how stem cell fate decisions are regulated in vivo. Elucidating the answer to this critical question in biology would facilitate the translation of the science of stem cell biology to the bedside for the development of novel therapies.

描述（由申请人提供）翻译后摘要：诱人的干细胞生物学的进步，导致了令人难以置信的新的治疗选择的一系列疾病的承诺。然而，现实情况是，持续的障碍迄今为止推迟了将再生医学的大多数潜在进展转化为临床，使其能够用于患者。这部分是因为缺少控制干细胞如何以及何时形成谱系（干细胞命运）和分化的工具。糖皮质激素，如皮质醇，天然激素，或作为药物使用的大量合成皮质醇类似物，在干细胞生物学中严重依赖，因为它们具有诱导细胞命运决定和前体细胞分化的强大能力。例如，糖皮质激素在体内和离体诱导脂肪细胞命运和分化中起关键作用。事实上，糖皮质激素对于理解干细胞分化的下游事件所取得的进展是不可或缺的。然而，糖皮质激素启动细胞命运决定的机制大多未被探索。在这里，我提出了一个新的范例，昼夜节律，控制24小时的身体节奏，是嵌入在糖皮质激素途径，是必不可少的调节干细胞的命运。为了验证我的假设，我将开发创新的跨学科工具来揭示干细胞，核激素受体和昼夜节律生物学之间的分子联系。从这些研究中获得的新知识将可能允许设计药物来指导选择性前体细胞沿着期望的和健康的分化谱系向下分化，远离疾病导向的路径。潜在的意义对于理解干细胞生物学的新方面和开发改进的药物来预防和/或治疗常见的衰弱性疾病如骨质疏松症，退化性肌肉疾病和糖尿病。公共卫生相关性：干细胞生物学领域的出现提高了再生医学的真实的潜力，为患有各种疾病的患者提供治疗和治愈，包括退行性肌肉疾病，骨质疏松症和糖尿病。这个项目的目标是测试一个假设，即干细胞的命运决定是如何在体内调节的。阐明生物学中这一关键问题的答案将有助于将干细胞生物学科学转化为新疗法的发展。