New Treatment Strategy for Alzheimer’s Disease

阿尔茨海默病的新治疗策略

• 批准号: 9981141
• 负责人: JIAN FENG
• 金额: $ 19.94万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9981141
• 关键词: Address; Affect; Age; Alzheimer disease screening; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Animals; Autopsy; Behavior; Behavioral; Behavioral Symptoms; Biochemical; Cognitive; Cognitive deficits; Data; Disease Progression; Dose; Electrophysiology (science); Enzymes; Epigenetic Process; Exhibits; Fibroblasts; Functional disorder; Gene Expression; Gene Expression Profile; Goals; Histone H3; Histones; Human; Impaired cognition; Intervention; Investigation; Lead; Link; Lysine; Mediating; Memory; Memory impairment; Methylation; Molecular; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Output; Pathogenesis; Pathologic; Patients; Pharmacology; Physiology; Post-Translational Protein Processing; Prefrontal Cortex; Role; Synapses; Testing; Therapeutic; Tissues; Transgenic Mice; Translating; Work; aging population; base; brief intervention; chromatin remodeling; demethylation; gene environment interaction; histone methylation; histone methyltransferase; histone modification; human disease; human stem cells; induced pluripotent stem cell; inhibitor/antagonist; insight; mouse model; novel; side effect; stem cells; synaptic function; targeted agent; tau Proteins; treatment strategy

Summary The goal of this study is to discover novel, mechanism-based pharmacological intervention for Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder. Emerging data suggest that epigenetic mechanisms are central to alterations in gene expression patterns and the ensuing synaptic dysfunctions and behavioral symptoms in AD. Our preliminary studies showed significantly elevated levels of histone modification mark H3K4me3 and its catalyzing enzyme Kmt3e in prefrontal cortex from AD human postmortem tissues and Tau transgenic mouse model of AD. We propose to investigate the hypothesis that Kmt3e inhibitors are able to ameliorate cognitive deficits associated with AD by normalizing gene expression and synaptic functions. To test this, both AD mouse models and AD patient-specific neurons will be used to address two specific aims with combined biochemical, molecular, electrophysiological and behavioral approaches. In Aim 1, we will identify the therapeutic potential of Kmt3e-targeting agents on cognitive and synaptic deficits in AD mouse models. To translate the findings from animal studies to AD patients, in Aim 2, we will generate and compare human neurons derived from AD patients and age-matched control subjects, and examine the capability of Kmt3e inhibitors to reverse synaptic deficits in AD human neurons. Results from this project may lead to new and effective pharmacological agents to treat cognitive and synaptic deficits of AD.

总结 本研究的目的是发现新的，基于机制的药物干预， 阿尔茨海默病（Alzheimer's disease，AD）是最常见的神经退行性疾病。新出现的数据表明， 表观遗传机制对基因表达模式的改变和随后的突触 功能障碍和行为症状。我们的初步研究显示， AD患者前额叶皮质组蛋白修饰标记H3K4me3及其催化酶Kmt3e 死后组织和AD的Tau转基因小鼠模型。我们建议调查的假设， Kmt3e抑制剂能够通过使基因表达正常化来改善与AD相关的认知缺陷 和突触功能。为了测试这一点，AD小鼠模型和AD患者特异性神经元都将被用于 结合生物化学、分子、电生理学和行为学， 接近。在目的1中，我们将确定Kmt3e靶向药物对认知和认知障碍的治疗潜力。 AD小鼠模型中的突触缺陷。为了将动物研究的结果转化为AD患者，在目标2中， 我们将产生并比较来自AD患者和年龄匹配的对照受试者的人类神经元， 并检查Kmt3e抑制剂逆转AD人类神经元中突触缺陷的能力。结果 该项目可能导致新的和有效的药理学试剂来治疗认知和突触缺陷， AD.