Epigenetic Reprogramming to Counteract Neuronal Aging and Degeneration

表观遗传重编程对抗神经元衰老和退化

• 批准号: 10039205
• 负责人: XIAO TIAN
• 金额: $ 11万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10039205
• 关键词: APP-PS1; Acute; Adult; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Area; Award; Axon; Behavioral; Bioinformatics; Birth; Blindness; Brain; Brain region; CNS degeneration; Candidate Disease Gene; Cell Cycle; Cell Survival; Cells; Characteristics; Chemicals; Chronic; Collaborations; Complex; Consultations; Crossbreeding; Crush Injury; DNA; DNA Methylation; Data; Dementia; Dependovirus; Deterioration; Development Plans; Disease; Ectopic Expression; Electrophysiology (science); Environment; Epigenetic Process; Etiology; Family health status; Gene Expression; Gene Silencing; Hippocampus (Brain); Histologic; Histological Techniques; Histone Acetylation; Histones; Impaired cognition; Impairment; In Vitro; Incidence; Injury; Knowledge; Learning; Link; Mammals; Mediating; Memory; Mentors; Mentorship; Modeling; Molecular; Molecular Structure; Mus; Natural regeneration; Nature; Nerve Degeneration; Nerve Regeneration; Neuraxis; Neurodegenerative Disorders; Neuronal Plasticity; Neurons; Neuropathy; Neurosciences; Optic Nerve; Pathogenesis; Pathologic; Patients; Phase; Physiological; Post-Translational Protein Processing; Property; Prosencephalon; Public Health; Rejuvenation; Research; Retina; Retinal Ganglion Cells; Retrieval; Role; Structure; Synaptic plasticity; System; Technology; Testing; Tetracyclines; Therapeutic; Therapeutic Effect; Training; Vincristine; Vision; Work; age related; aged; aging brain; axon regeneration; axonal degeneration; base; behavior test; career development; cell age; cognitive function; effective therapy; epigenome; epigenomics; experimental study; functional decline; genome-wide; genome-wide analysis; improved; inhibitor/antagonist; insight; medical schools; methylomics; mouse model; neuron loss; neuronal survival; neurophysiology; novel; pathological aging; prevent; programs; regenerative; therapeutic evaluation; transcriptome; transcriptome sequencing

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.

项目摘要/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。阿尔茨海默氏病（AD），主要 痴呆的形式是脑老化的极端病理表现。但是，病因和 AD的发病机理尚不清楚，导致有效治疗的死亡。越来越多的证据有 暗示的表观遗传变化，例如DNA甲基化和组蛋白乙酰化，神经元衰老和 退化，提出了重置这些表观遗传变化并恢复年轻表观基因组的假设 可能会增加神经可塑性和防止疾病。我们最近发现表观遗传重编程 通过共表达Yamanaka因子Oct4，Sox2和KLF4（OSK），可以诱导残留的轴突再生 急性损伤后，神经节细胞（RGC）是一种类型的中枢神经系统（CNS）神经元。此外，OSK 在旧小鼠的RGC中的表达反向衰老相关的转录组变化，重置DNA甲基化 细胞的年龄，并将视力恢复到类似于年轻小鼠的水平，表明神经元修订。 重要的是，细胞周期，细胞身份和有丝分裂神经元的内在电生理特性不是 受OSK重新编程的影响。在此提案中，我试图确定基于的表观遗传机制 OSK介导的轴突再生（AIM 1），确定表观遗传重编程是否在脑神经元中 逆转与年龄相关的认知下降和表观基因组变化（AIM 2），并研究 AD进展的表观遗传变化（AIM 3）。允许暂时控制的新鼠标模型 前脑神经元中的表观遗传重编程将用于评估表观遗传学的治疗作用 通过分子，物理，行为和组织学技术的组合在AD中重新编程。 根据我们的初步结果，我假设CNS神经元中衰老表观组的逆转将改善 神经元的可塑性和恢复认知功能受到衰老和阿尔茨海默氏病的损害。这 工作将为AD的病因提供新颖的见解，确定衰老与AD之间的表观遗传联系，以及 可能会揭示一个理论的新领域。目标1和2将主要在K99期间进行 在衰老和表观遗传学领导者戴维·辛克莱（David Sinclair）博士的心态下；爱德华·博伊登（Edward Boyden）博士，世界 - 著名的神经科学家； DNA甲基化和衰老专家Steve Horvath博士。 AIM 3将是 主要在R00阶段进行。 Mentalship计划和拟议的研究将使我 为了获得神经科学和生物信息学方面的严格科学培训，专门研究神经变性， 神经生理学和全基因组的表观遗传分析。另外，在哈佛进行K99阶段 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协作和咨询。奖项 将为我提供深入的职业发展计划，以扩大我的研究范围并启动 独立研究计划的重点是研究神经元衰老和变性的表观遗传机制。