TIP60 and APP in Neuronal Development

TIP60 和 APP 在神经元发育中的作用

• 批准号: 7904172
• 负责人: FELICE ELEFANT
• 金额: $ 25.12万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7904172
• 关键词: Acetylation; Adaptor Signaling Protein; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein Precursor; Apoptosis; Apoptosis Regulation Gene; Area; Behavioral; Biochemical; Biological Models; Biological Process; Brain; Cell Cycle Regulation; Cell Differentiation process; Cells; Chromatin; Chromatin Structure; Complement; Complex; Data; Development; Developmental Process; Disease; Dominant-Negative Mutation; Drosophila genus; Drosophila melanogaster; Enzymes; Epigenetic Process; Gene Activation; Gene Expression; Gene Expression Regulation; Gene Family; Gene Targeting; Genes; Genetic; Genetic Recombination; Goals; HTATIP gene; Histones; Homologous Gene; Human; Human Cloning; Knowledge; Laboratories; Link; Mediating; Mus; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neurons; Pathway interactions; Play; Process; Protein Overexpression; Proteins; Publishing; Qualifying; Recruitment Activity; Regulation; Repression; Research Personnel; Role; Signal Pathway; Signal Transduction; Staging; System; Techniques; Testing; Therapeutic; Tissues; Transcriptional Activation; Transcriptional Regulation; Transgenic Organisms; Up-Regulation; Work; base; cell type; developmental genetics; experience; fly; gene function; histone acetyltransferase; in vivo; nervous system development; neuron development; neuron loss; neurotoxicity; novel; overexpression; programs; promoter; protein complex; public health relevance; recombinational repair; success; transcription factor

DESCRIPTION (provided by applicant): Tip60 is a key histone acetyltransferase (HAT) enzyme that plays essential roles in diverse chromatin- mediated biological processes, including gene regulation, apoptosis, cell-cycle regulation, DNA recombination and repair. Tip60 is part of a multi-protein complex that is recruited by transcription factors to the promoters of certain genes where it generally acetylates surrounding histones to activate gene expression. Thus, Tip60 recruitment is involved in epigenetic gene regulation. While it is evident that Tip60 plays a central role in transcriptional control, it remains unclear as to the tissue and cell type-specific developmental pathways and target genes that require Tip60 to function. To investigate the role of TIP60 in multicellular development, our laboratory has identified and cloned the human TIP60 homolog in Drosophila (Dmel\TIP60). We have developed a system in transgenic flies that allows for targeted and inducible overexpression of wild-type or dominant negative HAT defective Dmel\TIP60 and Dmel\TIP60 knockdown in specific tissues, cell types and developmental stages of choice. Using this system, we have determined that Dmel\TIP60 is essential for nervous system formation during early development. We show that loss of Dmel\TIP60 in the fly brain leads to substantial neuronal loss and lethality. Consistent with our finding, other groups have documented an essential role for Tip60 HAT activity in the transcriptional activation of target genes via amyloid precursor protein (APP) mediated cell signaling pathways proposed to be involved in neuronal development. Intriguingly, TIP60 levels dramatically increase in the brains of young Alzheimer's disease (AD) model mice overproducing APP long before they acquire the A2 plaques, neurotoxicity and behavioral abnormalities representative of the disease. These findings provide the basis for our central hypothesis that APP perturbation causes upregulation of endogenous TIP60, leading to misregulation of both TIP60/APP and exclusive TIP60 chromatin-mediated neuronal pathways that is relevant in both development and neurodegeneration. To test this hypothesis, the following specific aims will be carried out. Aim 1 will identify TIP60 epigenetically regulated target genes that participate in distinct neuronal developmental processes and Aim 2 will determine the extent to which TIP60 chromatin-mediated neuronal processes and target genes are affected by overexpression of APP, in vivo. Such knowledge has important implications for the development of novel chromatin-based therapeutics in TIP60 associated disorders. PUBLIC HEALTH RELEVANCE: Our goal of deciphering the role of Tip60 and APP in neuronal development should profoundly enhance our understanding of nervous system development and neurodegenerative disorders. Such knowledge has important implications for the development of novel epigenetic-based therapeutics.

描述（申请人提供）：Tip60是一种关键的组蛋白乙酰转移酶（HAT）酶，在多种染色质介导的生物过程中发挥重要作用，包括基因调控、细胞凋亡、细胞周期调控、DNA重组和修复。Tip60是一个多蛋白复合物的一部分，它被转录因子招募到某些基因的启动子上，在那里它通常会使周围的组蛋白乙酰化以激活基因表达。因此，Tip60的募集参与了表观遗传基因调控。虽然很明显，Tip60在转录控制中起着核心作用，但仍不清楚组织和细胞类型特异性发育途径以及需要Tip60发挥作用的靶基因。为了研究TIP60在多细胞发育中的作用，我们实验室在果蝇中鉴定并克隆了人类TIP60同源基因（Dmel\TIP60）。我们已经在转基因果蝇中开发了一个系统，该系统允许在特定组织、细胞类型和发育阶段选择中靶向和诱导野生型或显性阴性HAT缺陷Dmel\TIP60和Dmel\TIP60敲低。使用该系统，我们已经确定Dmel\TIP60在早期发育期间对神经系统的形成至关重要。我们发现，果蝇大脑中Dmel\TIP60的缺失会导致大量神经元的丢失和死亡。与我们的发现一致，其他研究小组已经记录了Tip60 HAT活性在通过淀粉样前体蛋白（APP）介导的细胞信号通路参与神经元发育的靶基因转录激活中的重要作用。有趣的是，早在获得A2斑块、神经毒性和代表该疾病的行为异常之前，年轻阿尔茨海默病（AD）模型小鼠大脑中过量产生APP的TIP60水平就急剧增加。这些发现为我们的中心假设提供了基础，即APP扰动导致内源性TIP60上调，导致TIP60/APP和独有的TIP60染色质介导的神经元通路的失调，这些通路与发育和神经退行性变性有关。为了验证这一假设，将执行以下具体目标。Aim 1将确定参与不同神经元发育过程的TIP60表观遗传调控靶基因，Aim 2将确定体内APP过表达对TIP60染色质介导的神经元过程和靶基因的影响程度。这些知识对于开发新的基于染色质的治疗TIP60相关疾病的方法具有重要意义。公共卫生相关性：我们的目标是破译Tip60和APP在神经元发育中的作用，这将深刻地增强我们对神经系统发育和神经退行性疾病的理解。这些知识对于开发新的基于表观遗传学的治疗方法具有重要意义。