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（由申请人提供）：与衰老相关的迟发性慢性疾病，包括心血管疾病、痴呆、阿尔茨海默病和帕金森病、糖尿病和组织恶性肿瘤，是发病和死亡的主要原因，给个人和家庭造成最大的情感和经济负担。随着老龄化人口的扩大，迟发性慢性疾病将进一步引起生物医学和整个社会的关注，我们一直在继续研究大脑回路和体液因素在健康和衰老中的作用。我们和其他人已经确定，下丘脑神经元能够感知周围环境的变化，并发出信号，认为下丘脑是中枢神经系统和周围组织通讯之间的交叉点，定义了年轻和年老动物中差异表达的血清蛋白，并认识到心血管健康是寿命的主要决定因素。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回路来控制衰老过程。的控制饥饿以及其他复杂行为和外周组织功能的下丘脑对生存和寿命具有重大影响，我们还发现这些神经元介导与延长卡路里限制的影响有关的外周激素的作用。与年龄相关的中枢和外周过程中循环的老年物质至少部分是由下丘脑介导的，并且它们在下丘脑的功能能力中表现得至关重要 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的假定抗老年肽和蛋白质之间的明显差异（和一些相似之处）。为了评估我们使用非人灵长类成纤维细胞和非人灵长类 iPS 细胞衍生的细胞筛选中确定的假定老年靶标的细胞效应，我们将在灵长类动物中验证体内测试系统，以评估抗老年病和促老年病的干预措施。我们将分析已知的抗老年肽和促老年肽以及通过体外分析新定义的肽对具有广泛行为特征的年轻人（~4 岁）、中年人（~14 岁）和老年人的认知脑功能的影响。总体而言，我们的目标将提供有关老年物质的作用机制、新的循环老年分子的新见解，并建立和建立老年灵长类动物的心血管年龄。证实强大的测试系统将有助于与其他项目和研究人员进行协作，并将定义生物学推向临床相关应用。因此，我们相信我们的应用程序完全符合本 RFA 的文字和精神。