Integrated Healthspan Phenotyping

综合健康寿命表型

• 批准号: 10349483
• 负责人: ROBERT JOHN PIGNOLO
• 金额: $ 27.98万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10349483
• 关键词: AP20187; Accounting; Affect; Age; Aging; Animal Model; Animals; Archives; Behavioral; Biological; Biology of Aging; Biostatistics Core; Body Composition; CASP8 gene; Caloric Restriction; Cardiovascular Physiology; Cell Aging; Cell Death; Cells; Chimeric Proteins; Data; Data Element; Data Security; Databases; Development; Disease; Elderly; Ensure; Geroscience; Goals; Health; Histologic; Histology; Homeostasis; Human; Image; Immunologics; Individual; Inflammatory; Information Technology; Injury; Institutionalization; Lead; Longevity; Measures; Metabolic; Methods; Modeling; Morbidity - disease rate; Mus; Muscle; Natural regeneration; Outcome; Pathology; Performance; Pharmaceutical Preparations; Phenotype; Physical Function; Physiological; Process Measure; Property; Rattus; Records; Research Personnel; Risk Factors; Rodent; Site; Solid; Structure; System; T-Lymphocyte Subsets; Tissue Sample; Tissues; Transgenic Organisms; Translating; Treatment Efficacy; Work; cellular pathology; cellular targeting; clinical application; clinically relevant; cytokine; data management; data quality; data standards; design; disability; drug development; drug discovery; frailty; functional loss; functional status; healthspan; in vivo; indexing; innovation; novel; programs; promoter; resilience; sample archive; sample collection; senescence; skeletal; stressor; trait

CORE C: SUMMARY Pignolo The overall objective of Core C: Integrated Healthspan Phenotyping Core (IHPC) is to characterize novel animal models of senescent cell clearance by a variety of functional assessments across multiple domains. The IHPC will characterize two common models of senescent cell clearance in vivo, and integrate the use of these models across all four projects. One model will use the ATTAC cassette, which is a caspase-8/Fkbp fusion protein that causes cell death in the presence of the drug AP20187. In this model, a p16-INK-ATTAC transgenic rat model, the ATTAC cassette is driven by the p16 promoter. The second model is a physiological aging model treated with senotherapeutic drugs identified by Core B: Drug Discovery & Development. We anticipate that three or more potential senolytic (i.e., compounds that kill senescent cells)/senomorphic (i.e., compounds that inhibit the senescence-associated secretory phenotype [SASP]) drugs will be evaluated for effects on normal (physiologic) aging in mice. The lead senotherapeutic agent identified in mice will also be evaluated for healthspan benefits in the p16-INK-ATTAC transgenic rat model. These common animal models will be bred, maintained, and characterized for health span measures by the IHPC. By identifying animal models with extended health (e.g., models that reduce senescent cell burden) we will determine strategies capable of compressing morbidity as well as enhancing and extending health span in humans. The following functional domains related to Projects 1-4 will be assessed to characterize the healthspan across animal models: (i) metabolic homeostasis, body composition and energetics, (ii) skeletal integrity, (iii) cardiovascular function, (iv) muscle performance, and (v) immunologic/inflammatory status. A health index checklist will be utilized as a global assessment of functional status. These outcomes of healthspan have been selected for their stand-alone importance, clinical relevance, and established relationships with frailty, disability, institutionalization, and longevity in older persons. The ability to determine these outcomes in rodents will greatly enhance our ability to translate the basic biology of aging into clinical application-- the overarching goal of the Program Project. The IHPC will interact closely with Core D: Geroscience Pathology & Cellular Histology to facilitate examination of tissue samples from these models for a wide range of standard and innovative histological and pathophysiological analyses. The IHPC will also interact closely with Core A: Administrative and Biostatistics Core, to collect, curate, and manage data related to tissue sample collection, functional parameters, and histopathological findings as well as to oversee the distribution of animal models to Project Leads and other, non-PPG investigators, upon request.

核心C：总结Pignolo 核心C：整合Healthspan表型核心（IHPC）的总体目标是表征新的 通过跨多个领域的各种功能评估，建立衰老细胞清除的动物模型。 IHPC将表征体内衰老细胞清除的两种常见模型，并整合使用 这四个项目的模型。一个模型将使用ATTAC盒，其是半胱天冬酶-8/Fkbp的表达载体。 在药物AP 20187存在下导致细胞死亡的融合蛋白。在该模型中，p16-INK-ATTAC 在转基因大鼠模型中，ATTAC盒由p16启动子驱动。第二个模型是生理模型， 核心B：药物发现与开发。我们 预期三种或更多种潜在的衰老清除剂（即，杀死衰老细胞的化合物）/senomorphic（即， 将评价抑制衰老相关分泌表型的化合物[SASP]）药物的 对小鼠正常（生理）衰老的影响。在小鼠中鉴定的主要致敏剂也将在 在p16-INK-ATTAC转基因大鼠模型中评估健康持续益处。这些常见的动物模型 将由IHPC进行饲养、维护和表征，以进行健康寿命测量。通过识别动物 具有扩展健康的模型（例如，减少衰老细胞负担的模型），我们将确定策略 能够压缩发病率以及增强和延长人类的健康寿命。以下 将评估与项目1-4相关的功能域，以表征动物的健康寿命 模型：（i）代谢稳态，身体成分和能量，（ii）骨骼完整性，（iii）心血管 功能，（iv）肌肉性能，和（v）免疫/炎症状态。健康指数检查表将 用作功能状态的总体评估。healthspan的这些成果已被选定为 它们的独立重要性、临床相关性以及与虚弱、残疾 机构化和老年人的长寿。在啮齿类动物中确定这些结果的能力将 大大提高了我们将衰老的基础生物学转化为临床应用的能力--这是我们的首要目标， 的程序项目。IHPC将与核心D：老年科学病理学和细胞组织学密切互动 为了便于对来自这些模型的组织样本进行检查， 组织学和病理生理学分析。IHPC还将与核心A（行政）密切互动 和生物统计学核心，收集，策划和管理与组织样本收集，功能 参数和组织病理学发现，以及监督动物模型的分配到项目 根据要求，负责人和其他非PPG研究者。