Tissue-specific pharmacology to enhance healthspan

项目摘要/摘要 与老龄化相关的疾病是公共卫生面临的最大挑战之一。为了建立一个更健康的老龄化社会， 延长健康寿命的药物是当务之急。这类药物的开发可能会更加有效 对于老龄化人口来说，这比试图单独治疗与老龄化有关的疾病更重要。机械性的抑制 雷帕霉素靶标(MTOR)是一种进化保守的延缓衰老和延长寿命的策略。 也许最有希望和临床可翻译的延长健康寿命的方法是mTOR抑制 由小分子雷帕霉素引起。但对mTOR在年龄相关细胞中的作用的理解 缺乏系统一级的恶化，这阻碍了开发更安全和更有效的雷帕霉素 类比(Rapalog)。具体地说，由于缺乏针对特定细胞类型的雷帕霉素，它是 尚不清楚雷帕霉素在特定细胞类型中的活性如何在生物体中起到抗衰老作用 水平。这一根本的知识差距的广泛含义是发展的关键机会 可能会错过安全有效地延长健康寿命的治疗方法。这提供了一个强有力的理由 阐明特定细胞类型如何影响药物健康寿命和寿命延长的净结果 由雷帕霉素引起。我们的长期目标是确定哪些细胞类型与雷帕霉素有关 对延长健康寿命的影响，开发有针对性的mTOR抑制药理，从而使有效和 从长远来看，人类的安全健康寿命延长。 拟议项目的中心假设是雷帕霉素的延寿作用可以通过以下方式增强 这种药物只针对导致这些效应的特定组织。为了检验这一假说， 为了朝着我们的长远目标前进，我们提出了以下具体目标：(1)开发一种化学成因 可编程、细胞类型特异性靶向雷帕霉素的方法；(2)建立一种化学遗传的体内靶向 特定细胞类型的药物mTOR抑制平台；以及，(3)确定是否健康和寿命 选择性保留雷帕霉素可改善全身性、药理学mTOR抑制的益处 骨骼肌中mTOR的抑制作用。拟议的项目意义重大，因为它将使用创新的、 多学科方法，以解决未得到满足的医疗需求的主要领域。预计将进行拟议的研究 为了生产新的化学遗传工具和能够实现组织特异性、药理学mTOR抑制的Rapalog， 以及健康寿命指标和寿命的综合分析。我们预计拟议的研究将开启 通过产生组织特异性基因获得更有效的药物延长健康寿命的方法 MTOR抑制剂具有更好的临床疗效和安全性。

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.