Tissue-specific pharmacology to enhance healthspan

项目总结/摘要 与衰老有关的疾病是最大的公共卫生挑战之一。为了让老龄化社会更加健康， 急需延长健康寿命的药物。此类药物的开发可能会更加有效 而不是试图单独治疗与衰老有关的疾病。机械抑制 雷帕霉素靶蛋白（mTOR）是一种进化上保守的延缓衰老和延长寿命的策略。 也许最有前途和临床上可翻译的延长健康的方法是mTOR抑制 是由小分子雷帕霉素引起的但是了解mTOR在年龄相关的细胞中的作用， 缺乏系统水平的恶化，这阻碍了更安全和更有效的雷帕霉素的开发 类似物（Rapalogs）。具体地，由于缺乏将雷帕霉素靶向特定细胞类型的方法， 目前尚不清楚雷帕霉素在特定细胞类型中的活性如何有助于生物体的抗衰老作用， 水平这一根本性知识差距的广泛含义是， 安全有效的延长健康寿命的治疗方法可能会被错过。这为以下方面提供了强有力的理由： 阐明特定细胞类型如何影响药理学健康寿命和寿命延长的净结果 引起的我们的长期目标是确定哪些细胞类型负责雷帕霉素的 对延长健康寿命的作用，开发靶向mTOR抑制药理学，从而使有效和 安全的延长人类的健康寿命。 该项目的中心假设是，雷帕霉素的促长寿作用可以通过以下方式增强： 使药物仅靶向产生这些效应的特定组织。为了验证这一假设， 为了实现我们的长期目标，我们提出了以下具体目标：（1）发展化学遗传学 雷帕霉素的可编程的、细胞类型特异性靶向的方法;（2）建立化学遗传的、体内的 用于细胞类型特异性药理学mTOR抑制的平台;和，（3）确定健康寿命和寿命是否 通过选择性保留雷帕霉素， 抑制骨骼肌中mTOR。拟议的项目是重要的，因为它将使用创新， 多学科方法，以解决未满足的医疗需求的主要领域。这项研究预计 产生新的化学遗传工具和Rapalogs，使组织特异性，药理学mTOR抑制， 以及对健康寿命指标和寿命的全面分析。我们预计拟议的研究将开启 通过产生组织特异性的药物延长健康寿命的更有效方法的大门 具有改善的临床功效和安全性的mTOR抑制剂。

PROJECT SUMMARY/ABSTRACT Aging-related diseases are among the greatest public health challenges. To allow a healthier aging society, healthspan-extending drugs are critically needed. Development of such drugs will likely be vastly more effective for an aging population than attempting to treat aging-related diseases individually. Inhibition of mechanistic Target Of Rapamycin (mTOR) is an evolutionarily conserved strategy for slowing aging and extending lifespan. Perhaps the most promising and clinically translatable approach for healthspan extension is mTOR inhibition caused by the small molecule Rapamycin. But understanding of the role of mTOR in age-related cellular deterioration at the systems level is lacking, which prevents development of safer and more effective Rapamycin analogs (Rapalogs). Specifically, because of the lack of methods to target Rapamycin to specific cell types, it is not known how Rapamycin’s activity in particular cell types contributes to anti-aging effects at the organismal level. The broad implication for this fundamental gap in knowledge is that crucial opportunities for development of therapeutics for safe and effective healthspan extension may be missed. This provides a strong rationale for elucidating how specific cell types affect net outcomes of pharmacological healthspan and lifespan extension caused by Rapamycin. Our long-term goal is to determine which cell types are responsible for Rapamycin's effects on healthspan extension, develop targeted mTOR inhibition pharmacology, and thus enable effective and safe healthspan extension in humans in the longer term. The central hypothesis of the proposed project is that pro-longevity effects of Rapamycin can be enhanced by targeting the drug only to the specific tissues that are responsible for these effects. To test this hypothesis and to advance toward our long-term goal, we propose the following specific aims: (1) Develop a chemical-genetic approach for programmable, cell-type-specific targeting of Rapamycin; (2) Establish a chemical-genetic, in vivo platform for cell-type-specific pharmacological mTOR inhibition; and, (3) Determine if healthspan and lifespan benefits of systemic, pharmacological mTOR inhibition can be improved by selective sparing of Rapamycin's inhibition of mTOR in skeletal muscle. The proposed project is significant because it will use innovative, multidisciplinary approaches to address a major area of unmet medical need. The proposed study is expected to yield new chemical-genetic tools and Rapalogs enabling tissue-specific, pharmacological mTOR inhibition, and comprehensive analysis of healthspan metrics and lifespan. We expect the proposed study will open the door to more effective approaches for pharmacological extension of healthspan via generation of tissue-specific mTOR inhibitors with improved clinical efficacy and safety.