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: 9422316
• 负责人: TAMAS L HORVATH
• 金额: $ 53.6万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9422316
• 关键词: 14 year old; Address; Age; Aging; Aging-Related Process; Alcohol or Other Drugs use; Alzheimer' s Disease; Animals; Attention; Behavior; Behavioral; Biology; Blood; Brain; Caloric Restriction; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cell Aging; Chronic Disease; Cognitive; Cognitive aging; Communication; Complex; Data; Diabetes Mellitus; Elderly; Emotional; Evaluation; Event; Fibroblasts; Genotype; Health; Hormones; Human; Hunger; Hypothalamic structure; Impairment; In Vitro; Individual; Intervention; Isoproterenol; Learning; Letters; Longevity; Malignant Neoplasms; Mediating; Memory; Modeling; Morbidity - disease rate; Mus; Myocardium; Neurons; Nose; Oxytocin; Parabiosis; Parkinson Disease; Peptides; Peripheral; Physiological; Plasma; Preparation; Primates; Process; Proteins; Proteomics; Publishing; Rejuvenation; Research Personnel; Rodent; Role; Serum Proteins; Short-Term Memory; 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; insight; middle age; mortality; mouse model; nonhuman primate

Late onset chronic diseases associated with aging, including cardiovascular disorders, 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. 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. Our preliminary data and the work of others identified the same hypothalamic circuits to control the aging process. For example, we found that neurons of the hypothalamus that control hunger 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. We will interrogate this question using mouse models in Specific Aim 1. We will analyze complex behaviors, cardiac, muscle, bone and immune functions in control and experimental animals, including animals with different age and genotype in a state of parabiosis. From a translational perspective, it is crucial that the presence and relevance of geronic peptides are confirmed in higher species such as primates, including humans. In an effort to address this issue, we have analyzed plasma from young and aged nonhuman primates. Proteomics analysis identified candidate molecules in primates that have not been identified in mice. In Specific Aim 2, we propose to utilize our newly established, high throughput in vitro system to assess the cellular effects of putative geronic targets identified in our screen using nonhuman primate fibroblasts. We will focus on intracellular events that are associated with aging cells. In Specific Aim 3, we will test primates to evaluate anti- and pro-geronic interventions on CNS and cardiovascular systems. We will analyze the effects of young and aged plasma treatment of animals, known anti- and pro-geronic peptides and those newly defined by in vivo analyses on cognitive brain functions of young, middle aged and old nonhuman primates. Overall, execution of our aims will deliver new insights regarding the mechanisms of action of geronic substances, new circulating geronic molecules and exploit robust test systems that will lend themselves for collaborative work with other projects and investigators and the advance of defined biology to clinically relevant application.

与衰老相关的晚期发作慢性疾病，包括心血管疾病，阿尔茨海默氏症和 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 给个人和社会带来最大的情感和经济负担。作为人口老龄化 继续扩展，晚期慢性疾病将进一步主导生物医学的关注。我们 一直在追求大脑回路和健康因素在健康和衰老中的作用。我们已经确定了 下丘脑作为中枢神经系统和周围组织通信之间的相交点，定义血清 蛋白质在年轻动物和老年动物中差异表达，并确认心血管健康为主要 寿命的决定因素。我们和其他人已经确定下丘脑神经元感觉变化 外围环境，还发送信号以控制复杂的行为和器官系统和周围 组织功能。我们的初步数据和其他人的工作确定了相同的下丘脑电路 控制老化过程。例如，我们发现控制饥饿的下丘脑神经元具有 对生存和寿命的重大影响。我们还确定这些神经元介导了 外围激素与卡路里限制的寿命扩展有关。我们假设，那是 循环的慢性物质对与年龄相关的中央和外围过程的作用是介导的，至少至少 部分是下丘脑。我们将使用特定目标1中的鼠标模型来询问这个问题。我们 将分析复杂行为，心脏，肌肉，骨骼和免疫功能在对照和实验中 动物，包括在核心症状态下具有不同年龄和基因型的动物。来自翻译 透视，至关重要的是，在较高物种中证实了香肠肽的存在和相关性 例如灵长类动物，包括人类。为了解决这个问题，我们分析了Young的血浆 和年迈的非人类灵长类动物。蛋白质组学分析确定了未尚未的候选分子 在小鼠中被鉴定出来。在特定目标2中，我们建议利用我们新建立的高吞吐量 使用非人类的系统来评估我们屏幕上鉴定出的假定的geronic靶标的细胞效应 灵长类动物成纤维细胞。我们将专注于与衰老细胞相关的细胞内事件。在特定目标中 3，我们将测试灵长类动物，以评估中枢神经系统和心血管系统的抗挑剔干预措施。 我们将分析年轻和老化的血浆治疗动物的影响 肽和那些因体内对年轻，中年和 古老的非人类灵长类动物。总体而言，我们目标的执行将提供有关机制的新见解 香肠物质的作用，新的循环的Geronic分子和利用可借给的可靠测试系统 他们自己与其他项目和研究人员合作，以及定义的生物学的进步 临床相关的应用。