TIP60 and APP in Neuronal Development

TIP60 和 APP 在神经元发育中的作用

• 批准号: 7692988
• 负责人: FELICE ELEFANT
• 金额: $ 25.37万
• 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/7692988
• 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），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 是多蛋白复合物的一部分，由转录因子募集到某些基因的启动子，通常乙酰化周围的组蛋白以激活基因表达。因此，Tip60 招募参与表观遗传基因调控。虽然 Tip60 在转录控制中发挥着核心作用，但目前尚不清楚组织和细胞类型特异性的发育途径以及需要 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同源物（Dmel\TIP60）。我们在转基因果蝇中开发了一种系统，该系统允许在特定组织、细胞类型和所选发育阶段中对野生型或显性失活 HAT 缺陷 Dmel\TIP60 和 Dmel\TIP60 进行靶向和诱导性过表达。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。我们发现果蝇大脑中 Dmel\TIP60 的缺失会导致大量神经元损失和致死。与我们的发现一致，其他小组已经记录了 Tip60 HAT 活性在通过淀粉样前体蛋白 (APP) 介导的细胞信号传导途径转录激活靶基因中的重要作用，该信号通路被认为参与神经元发育。有趣的是，在年轻的阿尔茨海默病 (AD) 模型小鼠出现 A2 斑块、神经毒性和代表该疾病的行为异常之前，其大脑中的 TIP60 水平就急剧增加，这些小鼠过量产生 APP。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 和专有 TIP60 染色质介导的神经元通路的失调，这与发育和神经变性有关。为了检验这一假设，将实现以下具体目标。目标 1 将鉴定参与不同神经元发育过程的 TIP60 表观遗传调节靶基因，目标 2 将确定 TIP60 染色质介导的神经元过程和靶基因在体内受 APP 过度表达影响的程度。这些知识对于开发 TIP60 相关疾病的新型染色质疗法具有重要意义。 公共健康相关性：我们的目标是破译 Tip60 和 APP 在神经元发育中的作用，这应该会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。这些知识对于新型表观遗传学疗法的开发具有重要意义。