TIP60 and APP in Neuronal Development

TIP60 和 APP 在神经元发育中的作用

• 批准号: 8121617
• 负责人: FELICE ELEFANT
• 金额: $ 24.11万
• 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/8121617
• 关键词: Acetylation; Adaptor Signaling Protein; Affect; 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; DNA Repair; 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; Health; Histocompatibility Testing; 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; 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; gene repression; histone acetyltransferase; in vivo; nervous system development; neuron development; neuron loss; neurotoxicity; novel; overexpression; programs; promoter; protein complex; 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（由申请人提供）：Tip 60是一种关键的组蛋白乙酰转移酶（HAT），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。Tip 60是多蛋白复合物的一部分，其被转录因子募集到某些基因的启动子，在那里它通常乙酰化周围的组蛋白以激活基因表达。因此，Tip 60募集参与表观遗传基因调控。虽然Tip 60在转录调控中发挥着重要作用，但仍不清楚Tip 60发挥作用所需的组织和细胞类型特异性发育途径和靶基因。为了研究TIP 60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TIP 60同源物（Dmel\TIP60）。我们已经在转基因果蝇中开发了一种系统，该系统允许在特定组织、细胞类型和选择的发育阶段中靶向和诱导野生型或显性阴性HAT缺陷型Dmel\TIP60的过表达和Dmel\TIP60敲低。使用这个系统，我们已经确定Dmel\TIP60在早期发育过程中对神经系统的形成至关重要。我们表明，Dmel\TIP60在苍蝇大脑中的损失导致大量的神经元损失和致命性。与我们的发现一致，其他研究小组已经证明了Tip 60 HAT活性在靶基因的转录激活中的重要作用，该转录激活通过淀粉样前体蛋白（APP）介导的细胞信号传导途径进行，该途径被认为参与神经元发育。有趣的是，TIP 60水平在年轻的阿尔茨海默病（AD）模型小鼠的大脑中急剧增加，这些小鼠在获得A2斑块，神经毒性和代表该疾病的行为异常之前很久就过度产生APP。这些研究结果为我们的中心假设提供了基础，即APP扰动导致内源性TIP 60上调，导致TIP 60/APP和专有TIP 60染色质介导的神经元通路的失调，这与发育和神经退行性变有关。为了检验这一假设，将实现以下具体目标。目的1将确定TIP 60表观遗传调控的靶基因，参与不同的神经元发育过程和目的2将确定在何种程度上TIP 60染色质介导的神经元过程和靶基因的影响，过表达的APP，在体内。这些知识对开发新的基于染色质的治疗TIP 60相关疾病的药物具有重要意义。 公共卫生相关性：我们的目标是破译Tip 60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。这些知识对开发基于表观遗传学的新疗法具有重要意义。