Epigenetic Reprogramming to Counteract Neuronal Aging and Degeneration

项目总结/摘要 衰老的大脑越来越容易受到认知能力下降和痴呆症的影响。阿尔茨海默病（AD），一种主要的 痴呆症是大脑老化的一种极端病理表现。然而，病因和 AD的发病机制尚未得到很好的理解，导致缺乏有效的治疗。越来越多的证据表明 在神经元老化中涉及表观遗传变化，如DNA甲基化和组蛋白乙酰化， 退化，提出假设，重置这些表观遗传变化和恢复年轻的表观基因组 可以增加神经可塑性和预防疾病。我们最近发现表观遗传重编程 通过共表达三种Yamanaka因子Oct 4、Sox 2和Klf 4（OSK），可以诱导视网膜中的轴突再生， 神经节细胞（RGCs），一种中枢神经系统（CNS）神经元，在急性损伤后。此外，OSK 在老年小鼠RGCs中的表达逆转了衰老相关的转录组变化，重置了DNA甲基化， 年龄的细胞，并恢复视力的水平类似于年轻的小鼠，这表明神经元再生。 重要的是，有丝分裂后神经元的细胞周期、细胞身份和内在电生理特性并不 受到OSK重编程的影响在这个建议中，我试图确定表观遗传机制， OSK介导的轴突再生（Aim 1），确定脑神经元是否表观遗传重编程 逆转与年龄相关的认知能力下降和表观基因组变化（目标2），并研究 AD进展中的表观遗传变化（目的3）。一种新的小鼠模型，允许时间控制 前脑神经元中的表观遗传重编程将用于评估表观遗传治疗的疗效。 通过分子、生理、行为和组织学技术的组合，在AD中进行重编程。 基于我们的初步结果，我假设CNS神经元中衰老表观基因组的逆转将改善 神经可塑性和恢复认知功能，是由于老化和阿尔茨海默氏病受损。这 这项工作将为AD的病因学提供新的见解，确定衰老和AD之间的表观遗传联系， 可能会揭示一个新的治疗领域。目标1和2将主要在K99阶段执行 在大卫辛克莱博士的指导下，他是衰老和表观遗传学的领导者;爱德华博伊登博士，一个世界- 著名的神经科学家;史蒂夫·霍瓦特博士，DNA甲基化和衰老方面的专家。目标3将是 主要发生在R 00阶段。导师计划和拟议的研究将允许我 在神经科学和生物信息学方面获得严格的科学培训，专门研究神经变性， 神经生理学和全基因组表观遗传学分析。此外，在哈佛进行K99阶段时， 医学院，我的工作将受益于高度协作的研究环境，最先进的 技术和设施，以及世界知名的专家可用于合作和咨询。该奖项 将使我有一个深入的职业发展计划，以扩大我的研究范围，并推出一个 一个独立的研究项目，专注于研究神经元老化和退化的表观遗传机制。

Project Summary/Abstract The aging brain is increasingly susceptible to cognitive decline and dementia. Alzheimer’s disease (AD), a main form of dementia, is an extreme, pathological manifestation of brain aging. However, the etiology and pathogenesis of AD are not well understood, causing the dearth of effective treatments. Mounting evidence has implicated epigenetic changes, such as DNA methylation and histone acetylation, in neuronal aging and degeneration, raising the hypothesis that resetting these epigenetic changes and restoring a youthful epigenome may increase neuroplasticity and forestall disease. We have recently discovered that epigenetic reprogramming by coexpression of three Yamanaka factors, Oct4, Sox2, and Klf4 (OSK), can induce axon regeneration in retinal ganglion cells (RGCs), a type of central nervous system (CNS) neuron, after acute injury. Furthermore, OSK expression in RGCs of old mice reversed aging-associated transcriptome changes, reset the DNA methylation age of the cells, and restored vision to a level similar to young mice, suggesting neuronal rejuvenation. Importantly, cell cycle, cell identity, and intrinsic electrophysiological properties of postmitotic neurons were not affected by OSK reprogramming. In this proposal, I seek to identify the epigenetic mechanisms that underlie OSK-mediated axon regeneration (Aim 1), determine whether epigenetic reprogramming in brain neurons reverses age-associated cognitive decline and epigenomic changes (Aim 2), and investigate the role of epigenetic changes in the progression of AD (Aim 3). A new mouse model that allows temporal control of epigenetic reprogramming in the forebrain neurons will be used to evaluate the therapeutic effect of epigenetic reprogramming in AD through a combination of molecular, physiological, behavioral, and histological techniques. Based on our preliminary results, I hypothesize that reversal of the aging epigenome in CNS neurons will improve neuronal plasticity and restore cognitive function that are impaired due to aging and Alzheimer’s disease. This work will provide novel insights into the etiology of AD, identify the epigenetic links between aging and AD, and may reveal a new realm of therapeutics. Aims 1 and 2 will be performed predominantly during the K99 phase under the mentorship of Dr. David Sinclair, a leader in aging and epigenetics; Dr. Edward Boyden, a world- renowned neuroscientist; and Dr. Steve Horvath, an expert in DNA methylation and aging. Aim 3 will be performed predominantly during the R00 phase. The mentorship program and proposed research will allow me to gain rigorous scientific training in neuroscience and bioinformatics, specializing in neurodegeneration, neurophysiology, and genome-wide epigenetic analysis. In addition, in conducting the K99 phase at Harvard Medical School, my work will benefit from the highly collaborative research environment, state-of-the-art technologies and facilities, and world-renowned experts available for collaboration and consultation. The award will enable an in-depth career development plan for me to expand the scope of my research and launch an independent research program focused on studying epigenetic mechanisms of neuronal aging and degeneration.