In vivo and in vitro systems to validate geronic proteins and their mechanisms of action

用于验证老年蛋白及其作用机制的体内和体外系统

• 批准号: 9264636
• 负责人: TAMAS L HORVATH
• 金额: $ 49.38万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9264636
• 关键词: 14 year old; Activities of Daily Living; Address; Age; Aging; Aging-Related Process; Alcohol or Other Drugs use; Alzheimer' s Disease; Animal Model; Animals; Attention; Behavior; Behavioral; Biology; Blood; Brain; Caloric Restriction; Cardiovascular Diseases; Cardiovascular system; Cell Aging; Cells; Chronic Disease; Cognitive; Cognitive aging; Communication; Complex; Data; Dementia; Diabetes Mellitus; Disease; Elderly; Emotional; Environment; Evaluation; Fibroblasts; Health; Hormones; Human; Hunger; Hypothalamic structure; In Vitro; Individual; Intervention; Isoproterenol; Learning; Letters; Longevity; Malignant Neoplasms; Mediating; Memory; Molecular; Morbidity - disease rate; Mus; Myocardium; Neuraxis; Neurons; Parkinson Disease; Peptides; Peripheral; Physiological; Plasma; Preparation; Primates; Process; Proteins; Proteomics; Publishing; Rejuvenation; Research Personnel; Rodent; Role; Running; Serum Proteins; Signal Transduction; Societies; System; Testing; Thallium Myocardial Perfusion Imaging Stress Test; Time; Tissues; Work; age related; aged; aging population; body system; bone; cardiovascular health; clinically relevant; cohort; differential expression; immune function; in vivo; induced pluripotent stem cell; insight; middle age; mortality; mouse model; nonhuman primate

 DESCRIPTION (provided by applicant): Late onset chronic diseases associated with aging, including cardiovascular disorders, dementias, Alzheimer's and Parkinson's disease, diabetes and tissue malignancies, are the leading causes of morbidity and mortality creating the greatest emotional and financial burden on the individual and society. As the aging population continues to expand, late onset chronic diseases will further dominate the attention of biomedicine and society at large. We have been pursuing the role of the brain circuits and humoral factors in health and aging. We have identified the hypothalamus as an intersection point between CNS and peripheral tissue communications, defined serum proteins differentially expressed in young and old animals, and recognized cardiovascular health as a principal determinant of lifespan. We and others have established that hypothalamic neurons sense the changing peripheral milieu and also send out signals to control complex behaviors and organ system and peripheral tissue functions to appropriately adapt to changes in the environment. Our own preliminary data and the work of others have identified these same hypothalamic circuits to control the aging process. For example, we found that neurons of the hypothalamus that control hunger as well as other complex behaviors and peripheral tissue functions have significant impact on survival and lifespan. We also identified that these neurons mediate the action of peripheral hormones implicated in the lifespan extending impact of calorie restriction. We hypothesize that action of circulating geronic substances on age-related central and peripheral processes are mediated, at least in part, by the hypothalamus, and that they manifest critically in functional capacity of the cardiovascular, central nervous system and other critical organ systems. Our preliminary data revealed distinct differences (and some similarities) between circulating putative anti- and pro-geronic peptides and proteins between mice and nonhuman primates. We propose to establish a high throughput in vitro system to assess the cellular effects of putative geronic targets identified in our screen using nonhuman primate fibroblasts and cells derived from nonhuman primate iPS cells. We will validate in vivo test systems in primates to evaluate anti- and pro-geronic interventions on CNS and cardiovascular systems. We will analyze the effects of known anti- and pro-geronic peptides and those newly defined by in vitro analyses on cognitive brain functions of extensively behavioral characterized young (~4 years), middle aged (~14 years) and old (~30 years) nonhuman primates, and the modulation of cardiovascular age in old and young primates by similar putative geronic interventions. Overall, our aims will deliver new insights regarding the mechanisms of action of geronic substances, new circulating geronic molecules and establish and validate robust test systems that will lend themselves to collaborative work with other projects and investigators and the advance of defined biology to clinically relevant application. Thus, we believe that our application is fully responsive to the letter and spirit of this RFA.

 描述（由适用提供）：与衰老有关的晚期发作慢性疾病，包括心血管疾病，痴呆症，阿尔茨海默氏病和帕金森氏病，糖尿病和组织恶性肿瘤，是发病率和死亡率的主要原因，造成了对个人和社会的最大情感和财务燃烧。随着衰老人群的不断扩大，较晚的慢性疾病将进一步主导生物医学和整个社会的关注。我们一直在追求大脑电路和健康因素在健康和衰老中的作用。我们已经将下丘脑确定为中枢神经系统和周围组织通信之间的相交点，在年轻动物和老年动物中以不同表达的血清蛋白定义，并确认心血管健康是对寿命的主要决定。我们和其他人已经确定，下丘脑神经元感觉到周围环境的变化，并发出信号以控制复杂的行为和器官系统和外围组织功能，以适当适应环境变化。我们自己的初步数据和其他人的工作已经确定了这些相同的下丘脑电路以控制衰老过程。例如，我们发现，控制饥饿以及其他复杂行为和周围组织功能的下丘脑神经元对生存和寿命具有重大影响。我们还确定，这些神经元介导了在延长卡路里限制的寿命中实施的外围骑马的作用。我们假设循环的慢性物质对年龄相关的中央和外围过程的作用至少部分由下丘脑介导，并且它们以批判性表现为功能能力。 心血管，中枢神经系统和其他关键器官系统。我们的初步数据揭示了小鼠和非人类灵长类动物之间循环假定的抗蛋白胡椒和蛋白质之间的明显差异（以及一些相似之处）。我们建议使用非人类灵长类动物成纤维细胞和来自非人类灵长类动物IPS细胞的非人类灵长类动物成纤维细胞和细胞来评估在筛选中鉴定出的假定的geronic靶标的细胞效应。我们将私有验证体内测试系统，以评估中枢神经系统和心血管系统的抗蛋白干预措施。我们将分析已知的抗蛋白肽的影响，以及新定义的肽对广泛行为的认知大脑功能的新定义的影响，其年轻人（约4岁），中年（〜14岁）和旧（〜30岁）非人类灵长类动物，以及通过类似的Puttative Gericsic Interventions对老年和年轻的PRIME PRIME的调节。总体而言，我们的目标将提供有关Geronic物质，新循环的Geronic分子的作用机制的新见解，并建立和验证可靠的测试系统，这些测试系统将使自己与其他项目和研究人员合作，以及定义的生物学发展到临床相关的应用。这就是我们认为，我们的应用完全响应了该RFA的字母和精神。