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（由申请人提供）：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学过程中起着至关重要的作用，包括基因调节，凋亡，细胞周期调节，DNA重组和修复。 TIP60是一种多蛋白质复合物的一部分，该复合物是由转录因子募集到某些基因的启动子的募集的，在该基因中通常乙酰酸酯周围的组蛋白激活基因表达。因此，TIP60募集参与表观遗传基因调节。尽管很明显，TIP60在转录控制中起着核心作用，但对于需要TIP60才能运行的组织和细胞类型特异性发育途径和靶基因尚不清楚。为了研究TIP60在多细胞发育中的作用，我们的实验室已经确定并克隆了果蝇中的人类TIP60同源物（DMEL \ TIP60）。我们已经开发了一个转基因苍蝇的系统，该系统允许在特定组织，细胞类型和选择的发育阶段中野生型或显性负HAT有缺陷的DMEL \ TIP60和DMEL \ TIP60敲低的靶向和诱导过表达。使用该系统，我们确定DMEL \ TIP60对于早期发育过程中神经系统的形成至关重要。我们表明，蝇脑中DMEL \ TIP60的损失会导致大量神经元丧失和致死性。与我们的发现一致，其他小组已经记录了通过淀粉样蛋白前体蛋白（APP）介导的细胞信号传导途径在靶基因转录激活中的重要作用，并提出与神经元发育有关。有趣的是，TIP60水平在年轻的阿尔茨海默氏病（AD）模型小鼠的大脑中急剧增加，在获得A2斑块，神经毒性和行为异常的代表性之前，它们过量产生了应用。这些发现为我们的核心假设提供了基础，即应用扰动会导致内源性TIP60的上调，从而导致TIP60/APP和专有的TIP60染色质介导的神经元途径的不良调节，这与发育和神经变性相关。为了检验这一假设，将执行以下特定目标。 AIM 1将识别参与不同神经元发育过程的表观遗传调节的靶基因，AIM 2将决定tip60染色质介导的神经元过程的程度，而靶基因受体内过度表达的影响。这种知识对TIP60相关疾病中新型染色质治疗剂的发展具有重要意义。 公共卫生相关性：我们破译TIP60和APP在神经元发展中的作用的目标应深刻增强我们对神经系统发展和神经退行性疾病的理解。这种知识对基于表观遗传学的新型治疗学具有重要意义。