Integrated Healthspan Phenotyping

综合健康寿命表型

• 批准号: 10561626
• 负责人: ROBERT JOHN PIGNOLO
• 金额: $ 26.59万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10561626
• 关键词: AP20187; Accounting; Affect; Age; Aging; Animal Model; Animals; Archives; Behavioral; Biological; Biology of Aging; Biostatistics Core; Body Composition; Breeding; CASP8 gene; Caloric Restriction; Cardiovascular Physiology; Cell Aging; Cell Death; Cells; Chimeric Proteins; Data; Data Element; Data Security; Databases; Deterioration; 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; Property; Rat Transgene; Records; Research Personnel; Risk Factors; Rodent; Site; Solid; Structure; System; T-Lymphocyte Subsets; Tissue Sample; Tissues; Translating; Treatment Efficacy; Work; 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：摘要Pignolo 核心C的总体目标：集成的健康范围表型核心（IHPC）是表征新颖的 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将在体内表征两个常见的衰老细胞清除模型，并整合使用 这些模型在所有四个项目中。一种模型将使用ATTAC盒，即caspase-8/fkbp 在存在AP20187的情况下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，ATTAC盒由P16启动子驱动。第二个模型是生理 用核心B：药物发现与开发鉴定的鼻疗药物治疗的老化模型。我们 预计三种或更多的潜在鼻溶性（即杀死衰老细胞的化合物）/鼻型（即 将评估抑制与衰老相关的分泌表型[SASP]）药物的化合物 对小鼠正常（生理）衰老的影响。在小鼠中鉴定出的铅鼻骨疗法剂也将是 在p16-Ink-attac转基因大鼠模型中评估了健康范围的益处。这些常见的动物模型 将由IHPC繁殖，维护和表征健康跨度。通过识别动物 具有扩展健康的模型（例如，减轻衰老细胞负担的模型）我们将确定策略 能够压缩发病率，并增强和延长人类的健康范围。下列 将评估与项目1-4相关的功能域，以表征动物的健康范围 模型：（i）代谢稳态，身体成分和能量学，（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。健康指数清单将是 被用作全球功能状态评估。选择了HealthSpan的这些结果 他们独立的重要性，临床相关性以及与脆弱，残疾， 老年人的制度化和寿命。确定啮齿动物中这些结果的能力将 大大提高了我们将衰老基本生物学转化为临床应用的能力 - 总体目标 计划项目。 IHPC将与核心D：GEROSCIENCE病理学和细胞组织学紧密相互作用 促进从这些模型中检查各种标准和创新的组织样品 组织学和病理生理分析。 IHPC还将与核心A紧密互动：管理 和生物统计学核心，以收集，策划和管理与组织样品收集有关的数据 参数，组织病理学发现以及监督动物模型的分布 根据要求，领导和其他非PPG调查人员。