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

项目总结/摘要 衰老会导致成年人大脑的再生和认知障碍， 健康个体的神经退行性疾病。一个令人兴奋的可能性是利用再生的 成人大脑中干细胞逆转正常衰老和改善认知功能障碍的能力， 增强神经发生。我们和其他人已经表明，系统性操纵，如异时性操纵， 共生（其中年轻和年老动物的循环系统连接）或年轻血浆 给药可以部分逆转神经干/祖细胞（NPC）功能中与年龄相关的损伤， 老年大脑认知能力的丧失。有趣的是，异时共生研究显示， 年龄依赖性的双向性的影响，全身环境表明抗衰老因素， 年轻的血液会使人返老还童，而年老的血液中的促衰老因素会使人衰老。已经提出 减轻促衰老因素的影响也可能提供一种有效的方法来恢复衰老 表型，然而，缺乏对个体促衰老因子的功能研究。最近，我的实验室 鉴定了β2-微球蛋白（B2 M），一种主要组织相容性复合物1类（MHC I）分子的组分， 作为一种系统性的促衰老因子，对成年人的再生和认知功能进行负调节 海马体。这项研究的目的是从机制上了解 MHCI分子对衰老大脑的作用，并确定针对这些分子在老年人中的治疗潜力 年龄具体来说，我们的假设是B2 M与经典的MHC I分子一起作为促衰老因子 导致成年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：表征B2 M和MHC I下游与年龄相关的分子机制 成年人大脑中潜在的再生和认知增强。2：确定减少的有效性 细胞表面MHC I表达，以改善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，作为再生和认知的促衰老负调节因子， 在大脑中的功能。成功完成这些研究将具有重大的翻译潜力， 确定可以作为新疗法靶向的分子途径，以改善痴呆相关的 神经退行性疾病及其在受损的再生和 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.