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

描述(由申请人提供) 摘要：干细胞生物学取得了诱人的进展，为一系列疾病带来了令人难以置信的新治疗选择。然而，现实情况是，到目前为止，持续的障碍推迟了将再生医学中的大多数潜在进展转化为可用于患者的临床。这在一定程度上是因为缺少控制干细胞如何以及何时致力于谱系(干细胞的命运)和分化的工具。糖皮质激素，如天然激素皮质醇或大量用作药物的合成皮质醇类似物，由于其强大的诱导细胞命运决定和前体细胞分化的能力，在干细胞生物学中受到高度依赖。例如，糖皮质激素在体内和体外诱导脂肪细胞的命运和分化方面发挥着关键作用。事实上，糖皮质激素对于理解干细胞分化下游事件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尚不清楚。在这里，我提出了一个新的范例，即控制24小时身体节律的生物钟嵌入到糖皮质激素途径中，对调节干细胞的命运至关重要。为了验证我的假设，我将开发创新的跨学科工具，以揭示干细胞、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可能会使药物的设计能够引导选择性前体细胞沿着理想和健康的分化谱系前进，远离疾病导向的途径。这对于理解干细胞生物学的新方面，以及开发改进的药物来预防和/或治疗常见的衰弱疾病，如骨质疏松症、退行性肌肉疾病和糖尿病，都具有重要的潜在意义。 与公共卫生的相关性：干细胞生物学领域的出现提高了再生医学的真正潜力，为患有退行性肌肉疾病、骨质疏松症和糖尿病等一系列疾病的患者提供治疗和治愈。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受到调控的。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的科学转化为开发新疗法的床边。

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.