New Treatment Strategy for Alzheimer’s Disease

阿尔茨海默病的新治疗策略

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos 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

项目摘要

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.

概括本研究的目标是发现新颖的、基于机制的药理学干预措施阿尔茨海默病（AD）是最常见的神经退行性疾病，新数据表明。表观遗传机制对于基因表达模式和随后的突触改变至关重要我们的初步研究表明 AD 中的功能障碍和行为症状显着升高。 AD人前额皮质组蛋白修饰标记H3K4me3及其催化酶Kmt3e 我们建议研究 AD 的死后组织和 Tau 转基因小鼠模型。 Kmt3e 抑制剂能够通过使基因表达正常化来改善与 AD 相关的认知缺陷为了测试这一点，AD 小鼠模型和 AD 患者特异性神经元将被用于测试。通过结合生化、分子、电生理和行为来解决两个具体目标在目标 1 中，我们将确定 Kmt3e 靶向药物对认知和认知的治疗潜力。 AD 小鼠模型中的突触缺陷将动物研究的结果转化为 AD 患者，目标 2，我们将生成并比较来自 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 人类神经元突触缺陷的能力。该项目可能会产生新的有效药物来治疗认知和突触缺陷广告。