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

 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，是发病率和死亡率的主要原因，对个人和社会造成最大的情感和经济负担。随着人口老龄化的不断扩大，晚发性慢性病将进一步成为生物医学和社会关注的焦点。我们一直在研究脑回路和体液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外周组织通信之间的交叉点，定义血清蛋白在年轻和老年动物中的差异表达，并认识到心血管健康是寿命的主要决定因素。我们和其他人已经确定，下丘脑神经元可以感知周围环境的变化，并发出信号来控制复杂的行为、器官系统和外周组织功能，以适当地适应环境的变化。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回路来控制衰老过程。例如，我们发现控制饥饿以及其他复杂行为和外周组织功能的下丘脑神经元对生存和寿命有显着影响。我们还发现，这些神经元介导了外周激素的作用，这些激素与热量限制对延长寿命的影响有关。我们推测，循环老年物质对年龄相关的中枢和外周过程的作用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起关键作用。 心血管、中枢神经系统和其他重要器官系统。我们的初步数据显示，小鼠和非人灵长类动物之间的循环推定的抗-和pro-geronic肽和蛋白质之间的明显差异（和一些相似之处）。我们建议建立一个高通量的体外系统，以评估在我们的屏幕上使用非人灵长类动物的成纤维细胞和细胞来源于非人灵长类动物的iPS细胞确定的推定的老年目标的细胞效应。我们将在灵长类动物中验证体内测试系统，以评估对CNS和心血管系统的抗衰老和促衰老干预。我们将分析已知的抗-和pro-geronic肽和那些新定义的广泛行为特征的年轻（~4岁），中年（~14岁）和老年（~30岁）的非人灵长类动物的认知脑功能的体外分析的影响，和老年和年轻灵长类动物的心血管年龄的调制类似的推定老年干预。总的来说，我们的目标将提供有关老年物质作用机制的新见解，新的循环老年分子，并建立和验证强大的测试系统，这些系统将有助于与其他项目和研究人员的合作，并将定义生物学推向临床相关应用。因此，我们认为，我们的申请完全符合该RFA的文字和精神。

 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.