Tissue-specific pharmacology to enhance healthspan

组织特异性药理学可延长健康寿命

• 批准号: 10445523
• 负责人: KEVAN M. SHOKAT
• 金额: $ 33.11万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10445523
• 关键词: Acute; Address; Adverse effects; Affect; Aging; American; Animals; Applications Grants; Area; Binding; Biology; Biology of Aging; CCI-779; Caloric Restriction; Cardiovascular Diseases; Cells; Chemicals; Communities; Cre driver; Deterioration; Development; Disease; Drug Targeting; Economic Burden; Elderly; FDA approved; FRAP1 gene; Foundations; Generations; Genetic; Goals; Human; Individual; Knock-in Mouse; Knock-out; Knowledge; Longevity; Malignant Neoplasms; Measures; Mediating; Medical; Metabolic; Methods; Mission; Mus; Muscular Atrophy; Natural Products; Nerve Degeneration; Outcome; Pharmaceutical Preparations; Pharmacology; Phenotype; Population; Positioning Attribute; Proteins; Public Health; Research; Resources; Risk Factors; Role; Safety; Signal Transduction; Sirolimus; Site; Skeletal Muscle; Societies; System; Tacrolimus Binding Protein 1A; Technology; Testing; Therapeutic; Tissues; United States National Institutes of Health; age effect; age related; aging population; analog; anti aging; cell type; chemical genetics; clinical efficacy; clinically translatable; cohort; design; genetic approach; healthspan; human old age (65+); improved; in vivo; inhibitor/antagonist; innovation; interdisciplinary approach; middle age; muscle form; mutant; prevent; programs; sex; side effect; small molecule; therapeutic development; tool

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.

项目概要/摘要 与老龄化相关的疾病是最大的公共卫生挑战之一。 迫切需要延长健康寿命的药物，这种药物的开发可能会更加有效。 针对人口老龄化，而不是尝试单独治疗与衰老相关的疾病。 雷帕霉素靶标 (mTOR) 是一种进化上保守的减缓衰老和延长寿命的策略。 也许延长健康寿命最有前途且可临床转化的方法是 mTOR 抑制 由小分子雷帕霉素引起，但了解 mTOR 在年龄相关细胞中的作用。 系统层面的恶化程度不存在，这阻碍了更安全、更有效的雷帕霉素的开发 具体来说，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机体的抗衰老作用 这种基本知识差距的广泛含义是发展的重要机遇。 可能会错过安全有效延长健康寿命的治疗方法，这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延长寿命的净结果 我们的长期目标是确定哪些细胞类型是雷帕霉素引起的。 延长健康寿命的影响，开发有针对性的 mTOR 抑制药理学，从而实现有效和 从长远来看，延长人类的安全健康寿命。 该项目的中心假设是雷帕霉素的延长寿命作用可以通过以下方式增强： 仅将药物靶向导致这些作用的特定组织，以检验这一假设并进行验证。 为了实现我们的长期目标，我们提出以下具体目标：（1）开发化学遗传学 雷帕霉素的可编程、细胞类型特异性靶向方法；(2) 建立体内化学遗传方法； 细胞类型特异性药理学 mTOR 抑制的平台；以及，(3) 确定健康寿命和寿命 通过选择性保留雷帕霉素的作用，可以改善全身性药理学 mTOR 抑制的益处 抑制骨骼肌中的 mTOR 所提出的项目意义重大，因为它将使用创新的、 预计拟议的研究将采用多学科方法来解决未满足的医疗需求的主要领域。 产生新的化学遗传工具和 Rapalogs，实现组织特异性、药理学 mTOR 抑制， 我们预计拟议的研究将开启健康寿命指标和寿命的综合分析。 通过生成组织特异性药物，获得更有效的药物延长健康寿命的方法之门 mTOR抑制剂具有改善的临床疗效和安全性。