Mechanisms underlying Tip60 HAT action in neuroprotection of cognitive function

Tip60 HAT 认知功能神经保护作用的机制

• 批准号: 10577720
• 负责人: FELICE ELEFANT
• 金额: $ 114.54万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10577720
• 关键词: Acetylation; Age Factors; Alternative Splicing; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Amyloid beta-Protein Precursor; Area; Award; Behavioral Assay; Binding; Bioinformatics; Biological Assay; Biological Models; Brain; Cell Nucleus; Chromatin; Cognition; Cognitive; Complement; Complex; Defect; Dementia; Disease Progression; Drosophila genus; Environmental Risk Factor; Enzymes; Epigenetic Process; Etiology; Exhibits; Exposure to; Funding; Genes; Genetic; Genetic Transcription; Genomics; Goals; Hippocampus (Brain); Histone Acetylation; Histone Deacetylase; Histones; Human; Impaired cognition; Impairment; In Vitro; Laboratories; Link; Mediating; Mediator of activation protein; Memory; Memory impairment; Modeling; Molecular; Mutagenesis; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neuronal Plasticity; Neurons; Neurophysiology - biologic function; Nuclear Import; Pathway interactions; Pharmacological Treatment; Pharmacology; Process; Publishing; RNA; RNA Binding; RNA Splicing; Rattus; Regulator Genes; Research; Role; Severities; Structural Models; Surface Plasmon Resonance; Synapses; Systems Biology; Testing; Therapeutic; Transgenic Organisms; base; chemical binding; cognitive benefits; cognitive function; drug discovery; early detection biomarkers; experience; extracellular; fly; histone acetyltransferase; in silico; in vivo; interest; mild cognitive impairment; neural circuit; neuroprotection; novel; novel therapeutics; nucleocytoplasmic transport; relating to nervous system; response; side effect; targeted biomarker; transcriptome; transcriptomics

ABSTRACT Alzheimer’s disease (AD) is a debilitating progressive neurodegenerative disorder (ND) hallmarked by initial mild cognitive impairment (MCI) followed by dementia. The severity of AD progression is dependent upon the complex interplay between genetics, age, and environmental factors orchestrated in large part, by epigenetic histone acetylation (HA) mediated gene regulatory mechanisms. HA homoeostasis in the brain is maintained by antagonizing histone acetyltransferase (HAT) and histone deacetyltransferase (HDAC) enzymes that generate and erase cognition-linked histone acetylation marks, respectively. Reduced HA levels in the brain cause chromatin packaging alterations in neurons, with concomitant transcriptional dysregulation that is a key initial step in AD etiology. Nevertheless, the specific HATs that generate these distinct neuroepigenomic acetylation signatures in the brain, and thus serve as causative agents underlying memory impairing HA alterations in AD, remain largely unknown. Our laboratory has a long-standing interest in the HAT Tip60 as an epigenetic mediator of neural transcriptional regulatory responses in cognition and AD. We generated a robust APP;Tip60 Drosophila model system that enables us to modulate Tip60 HAT levels in neural circuits of choice under AD amyloid precursor protein (APP) neurodegenerative conditions, in vivo. Its use led to a compendium of published studies that establish a central role for Tip60 HAT mediated chromatin dynamics in cognitive function and neuroprotection in AD. During this funding period, we also made several separate and striking discoveries regarding alternative novel cellular mechanisms for Tip60 in mediating neuronal gene control that are disrupted in AD. These include: (1) experience-dependent (ED) Tip60 nucleocytoplasmic transport (NCT) and (2) a novel RNA-binding function for Tip60. The overarching goal of this proposal is to elucidate these new Tip60 functions, as well as generate novel Tip60 specific therapeutic compounds, to deepen our understanding of Tip60’s unique roles in nervous system biology and AD neuroprotection. To achieve this research goal, our team combines expertise in the unique but complementing areas of Tip60 function in cognition and AD (Elefant, PI), neuroepigenetics in RNA splicing (Heller, CoI) and novel drug discovery (Kortegare, CoI) to propose the following specific aims: In Aim 1 we functionally assess Tip60 nucleocytoplasmic transport (NCT) in neuronal experience- dependent gene control. In Aim 2 we dissect a novel bi-level neuronal function for Tip60 at the chromatin and RNA splicing level in †he brain. In Aim 3 we will generate novel Tip60 based therapeutic compounds to identify cognitive benefits of pharmacologically enhancing human Tip60’s HAT activity. Successful completion of this project will uncover novel molecular pathways, targets and early biomarkers to treat AD and generate a specific Tip60 HAT activator compound with AD neuroprotection capabilities.

摘要 阿尔茨海默病（AD）是一种衰弱性进行性神经退行性疾病（ND），其特征在于 最初的轻度认知障碍（MCI），随后是痴呆。AD进展的严重程度取决于 遗传、年龄和环境因素之间复杂的相互作用，在很大程度上是由表观遗传学所安排的。 组蛋白乙酰化（HA）介导的基因调控机制。HA在脑中的稳态是通过 拮抗组蛋白乙酰转移酶（HAT）和组蛋白脱乙酰转移酶（HDAC）， 和擦除认知相关的组蛋白乙酰化标记。大脑中HA水平的降低会导致 神经元中的染色质包装改变，伴随着转录失调，这是关键的初始步骤 在AD病因学中。然而，产生这些不同的神经表观基因组乙酰化的特定HAT 在大脑中的签名，并因此作为致病剂潜在的记忆损害HA改变在AD中， 但基本上仍不为人所知。我们的实验室长期以来一直对HAT Tip 60作为表观遗传介质感兴趣 认知和AD中的神经转录调节反应。我们生成了一个强大的APP; Tip 60果蝇 模型系统，使我们能够调节AD淀粉样蛋白下选择的神经回路中的Tip 60 HAT水平 前体蛋白（APP）的神经退行性疾病，在体内。它的使用导致了一个已发表研究的简编 这确立了Tip 60 HAT介导的染色质动力学在认知功能中的中心作用， AD的神经保护作用在这段资助期间，我们还取得了几项独立而惊人的发现 关于Tip 60在介导神经元基因控制中的替代性新细胞机制， AD.这些包括：（1）经验依赖性（艾德）Tip 60核质转运（NCT）和（2）一种新的 Tip 60的RNA结合功能。本提案的首要目标是阐明这些新的Tip 60功能， 以及产生新的Tip 60特异性治疗化合物，以加深我们对Tip 60独特的 神经系统生物学和AD神经保护作用。为了实现这一研究目标，我们的团队结合了 在Tip 60在认知和AD中功能的独特但互补领域的专业知识（Elefant，PI）， RNA剪接中的神经表观遗传学（Heller，CoI）和新药发现（Kortegare，CoI）提出以下建议 具体目标：在目标1中，我们在神经元体验中功能性评估Tip 60核质转运（NCT）- 依赖基因控制在目标2中，我们剖析了Tip 60在染色质和细胞核中的一种新的双水平神经元功能。 大脑中的RNA剪接水平。在目标3中，我们将产生新的基于Tip 60的治疗化合物，以鉴定 增强人类Tip 60的HAT活性。成功完成本 该项目将揭示新的分子途径，目标和早期生物标志物来治疗AD，并产生一种特异性的 具有AD神经保护能力的Tip 60 HAT激活剂化合物。