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

 描述(申请人提供)：与老龄化相关的迟发性慢性疾病，包括心血管疾病、痴呆症、阿尔茨海默氏症和帕金森氏病、糖尿病和组织恶性肿瘤，是导致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。随着老龄化人口的不断扩大，迟发性慢性病将进一步主导生物医学和整个社会的关注。我们一直在研究大脑回路和体液因素在健康和衰老中的作用。我们已经确定下丘脑是中枢神经系统和外周组织交流的交叉点，确定了在幼年和老年动物中差异表达的血清蛋白，并认识到心血管健康是决定寿命的主要因素。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，也可以发出信号来控制复杂的行为以及器官系统和外围组织的功能，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围组织功能的下丘脑神经元对生存和寿命有重大影响。我们还发现，这些神经元介导了外周激素的作用，这些外周激素与卡路里限制延长寿命的影响有关。我们假设，循环中的老年物质在与年龄相关的中枢和外周过程中的作用至少部分是由下丘脑介导的，它们关键地表现在大脑的功能能力上。 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，在小鼠和非人类灵长类动物之间，循环中假定的抗老年肽和促老年肽和蛋白质之间存在明显的差异(和一些相似之处)。我们建议建立一个高通量的体外系统，以评估在我们的筛选中确定的可能的老年靶点的细胞效应，使用非人灵长类成纤维细胞和来自非人灵长类iPS细胞。我们将验证灵长类动物的体内测试系统，以评估对中枢神经系统和心血管系统的抗老年和促老年干预措施。我们将分析已知的抗老年肽和促老年肽以及体外分析新定义的那些对具有广泛行为特征的青年(~4岁)、中年(~14岁)和老年(~30岁)非人类灵长类动物认知脑功能的影响，以及类似的假定的老年干预对老年和年轻灵长类动物心血管年龄的调节。总体而言，我们的目标将提供关于老年物质、新的循环老年分子的作用机制的新见解，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合作，并推动定义生物学应用于临床。因此，我们相信，我们的申请完全符合本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.