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.

项目摘要/摘要 与衰老有关的疾病是最大的公共卫生挑战之一。为了允许一个更健康的衰老社会， 至关重要的是，健康范围扩展药物。这种药物的开发可能会更有效 对于老年人口而言，试图单独治疗与衰老有关的疾病。抑制机械 雷帕霉素（MTOR）的靶标是一种进化配置的策略，可减缓衰老和延长寿命。 也许最有前途和临床可以翻译的健康范围扩展方法是mtor抑制作用 由小分子雷帕霉素引起。但是了解MTOR在与年龄相关的细胞中的作用 缺乏系统级别的恶化，这阻止了更安全，更有效的雷帕霉素的发展 类似物（Rapalogs）。具体而言，由于缺乏将雷帕霉素靶向特定细胞类型的方法，因此 尚不清楚雷帕霉素在特定细胞类型中的活性如何促进有机体的抗衰老作用 等级。知识中这种基本差距的广泛含义是发展的关键机会 从理论上讲，可能会错过安全有效的健康范围扩展。这为 阐明特定细胞类型如何影响药品健康范围和寿命扩展的净结果 由雷帕霉素引起。我们的长期目标是确定哪些细胞类型负责雷帕霉素 对HealthSpan扩展的影响，开发了针对MTOR抑制药理学，从而实现有效和 从长远来看，人类的安全健康范围扩展。 拟议项目的核心假设是，雷帕霉素的促态效应可以通过 仅针对这些影响这些作用的特定组织。检验这一假设和 为了朝着我们的长期目标迈进，我们提出以下特定目标：（1）开发一种化学遗传 雷帕霉素的可编程，特定于细胞类型的靶向方法； （2）建立一个化学基因体内体内 细胞型特异性药物MTOR抑制的平台； （3）确定健康范围和寿命是否 通过选择性保留雷帕霉素可以改善系统性，药物MTOR抑制的好处 在骨骼肌中抑制MTOR。拟议的项目很重要，因为它将使用创新， 多学科的方法来解决未满足医疗需求的主要领域。拟议的研究预计 为了产生新的化学遗传学工具和旋转型，可实现组织特异性的药物MTOR抑制作用， 以及对健康范围指标和寿命的全面分析。我们预计拟议的研究将打开 通过组织特异性的生成，通往健康范围的药物扩展的更有效方法 MTOR抑制剂提高了临床效率和安全性。