Investigating the pro-aging role of B2M and MHC molecules on regenerative and cognitive function in the brain

项目摘要/摘要 衰老导致成人大脑中的再生和认知损伤，增加了对 健康个体的神经退行性疾病。一种令人兴奋的可能性是利用可再生能源 成人脑内干细胞逆转正常衰老和改善认知功能障碍的能力 促进神经发生。我们和其他人已经证明，系统的操纵，如异时 异种共生(幼年和老年动物的循环系统连接在一起)或幼年血浆 给药可以部分逆转与年龄相关的神经干细胞/祖细胞(NPC)功能损害，并 老年人大脑中认知能力的丧失。有趣的是，异慢性异种异生研究揭示了一种 抗衰老因素在全身环境中的年龄依赖性双向影响 年轻的血液会激发活力，而老年血液中的促衰老因素则会促使衰老。有人提议， 减轻促衰老因素的影响也可能为延缓衰老提供有效的途径。 然而，缺乏对单个促衰老因子的功能研究。最近我的实验室 鉴定出β2-微球蛋白(B2M)，它是主要组织相容性复合体1类(MHC I)分子的组成部分， 作为一种全身性促衰老因子，对成人的再生和认知功能具有负面调节作用 海马体。这项拟议的研究的目的是从机理上深入了解黄连素的抗衰老作用。 MHC I分子在衰老的大脑中的作用，并确定针对这些分子在老年的治疗潜力 年龄。具体地说，我们的假设是B2M与经典的MHC I分子协同起到促进衰老的作用 驾驶成人海马体中与年龄相关的再生和认知障碍。我们将检验这一理论 有三个具体目标：1：研究B2M和MHC I下游与年龄相关的分子机制 在成人大脑中潜在的再生和认知增强。2：确定减排的有效性 细胞表面MHC I的表达以改善与年龄相关的再生和认知障碍。3：调查 经典的MHC I分子H2-KD和H2-DB作为促进衰老的再生和认知负调控因子 大脑的功能。成功完成这些研究将具有巨大的翻译潜力， 确定可作为改善痴呆相关新疗法的靶点的分子途径 神经退行性疾病及其下游后果--再生能力受损和 认知功能。

PROJECT SUMMARY/ABSTRACT Aging drives regenerative and cognitive impairments in the adult brain, increasing susceptibility to neurodegenerative disorders in healthy individuals. One exciting possibility is to harness the regenerative capacity of stem cells in the adult brain to reverse normal aging and ameliorate cognitive dysfunction by enhancing neurogenesis. We, and others, have shown that systemic manipulations such as heterochronic parabiosis (in which the circulatory system of a young and old animal are joined) or young plasma administration can partially reverse age-related impairments in neural stem/progenitor cell (NPC) function and loss of cognitive faculties in the aged brain. Interestingly, heterochronic parabiosis studies have revealed an age-dependent bi-directionality in the influence of the systemic environment indicating anti-aging factors in young blood elicit rejuvenation while pro-aging factors in old blood drive aging. It has been proposed that mitigating the effect of pro-aging factors may also provide an effective approach to rejuvenate aging phenotypes, however functional investigation of individual pro-aging factors is lacking. Recently my lab identified β2-microglobulin (B2M), a component of major histocompatibility complex class 1 (MHC I) molecules, as a systemic pro-aging factor that negatively regulates regenerative and cognitive functions in the adult hippocampus. The purpose of the proposed study is to gain mechanistic insight into the pro-aging effects of MHC I molecules on the aging brain, and ascertain the therapeutic potential of targeting these molecules at old age. Specifically, our hypothesis is that B2M in concert with classical MHC I molecules act as pro-aging factors driving age-related regenerative and cognitive impairments in the adult hippocampus. We will test this theory with Three Specific Aims: 1: Characterize age-related molecular mechanisms downstream of B2M and MHC I underlying regenerative and cognitive enhancements in the adult brain. 2: Determine effectiveness of reducing cell surface MHC I expression to ameliorate age-related regenerative and cognitive impairments. 3: Investigate classical MHC I molecules, H2-Kd and H2-Db, as pro-aging negative regulators of regenerative and cognitive function in the brain. Successful completion of these studies will have significant translational potential, identifying molecular pathways that could be targeted for novel therapies to ameliorate dementia-related neurodegenerative disorders and their downstream consequences in terms of impaired regenerative and cognitive functions.