Integrated Healthspan Phenotyping

核心C：Pignolo摘要 核心C：集成Healthspan表型核心(IHPC)的总体目标是描述新的 通过跨多个领域的各种功能评估的衰老细胞清除的动物模型。 IHPC将描述两种常见的体内衰老细胞清除模型，并整合使用 这些模型涵盖了所有四个项目。其中一个型号将使用ATTAC盒式磁带，这是一种caspase-8/FkBP 在药物AP20187存在时导致细胞死亡的融合蛋白。在此模型中，p16-ink-ATTAC 转基因大鼠模型中，ATTAC盒由p16启动子驱动。第二种模式是生理学的 由核心B：药物发现与开发确定的老年治疗药物治疗衰老模型。我们 预期三个或更多潜在的感觉剂(即，杀死衰老细胞的化合物)/感觉性(即， 将对抑制衰老相关分泌表型[SASP]药物的化合物进行评估 对小鼠正常(生理)衰老的影响。在老鼠身上发现的铅感官治疗剂也将是 在p16-ink-ATTAC转基因大鼠模型中评估健康寿命效益。这些常见的动物模型 将由IHPC根据健康寿命措施进行繁殖、维护和表征。通过识别动物 延长健康状态的模型(例如，减少衰老细胞负担的模型)我们将确定策略 能够降低发病率以及增强和延长人类的健康寿命。以下是 将评估与项目1-4相关的功能域，以表征动物的健康跨度 模型：(一)代谢动态平衡、身体组成和能量学，(二)骨骼完整性，(三)心血管 功能，(Iv)肌肉表现，和(V)免疫/炎症状态。健康指数核对表将是 作为对职能状况的全球评估。这些健康寿命的结果被选为 它们的独立重要性、临床相关性以及与虚弱、残疾、 老年人的制度化和长寿。在啮齿动物身上确定这些结果的能力将 极大地增强我们将衰老的基本生物学转化为临床应用的能力--首要目标 该计划项目的。IHPC将与核心D：老年学病理学和细胞组织学密切互动 以便于对这些模型的组织样本进行广泛的标准和创新检查 组织学和病理生理学分析。IHPC还将与核心A密切互动：行政 和生物统计核心，用于收集、整理和管理与组织样本收集相关的数据，功能 参数和组织病理学结果，以及监督动物模型到项目的分布 线索和其他非PPG调查人员，应要求。

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.