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TIP60 and APP in Neuronal Development

TIP60 和 APP 在神经元发育中的作用

基本信息

批准号：
8318766
负责人：
FELICE ELEFANT
金额：
$ 24.24万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-30 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8318766
关键词：
Acetylation Adaptor Signaling Protein Affect Alzheimer&apos 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 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

项目摘要

Principle Investigator/Program Director (Last, first, middle) Elefant, Felice ABSTRACT: TIP60 and APP in neuronal development 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 A¿ 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. PHS 398/2590 (Rev. 05/01) Page _____ Continuation Format Page Principle Investigator/Program Director (Last, first, middle) Elefant, Felice NARRATIVE: 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. PHS 398/2590 (Rev. 05/01) Page _____ Continuation Format Page

首席调查员/项目主任(最后、第一、中间)Elefant，Felice 摘要：Tip60和APP在神经元发育中的作用 Tip60是组蛋白乙酰转移酶(HAT)的关键酶，在多种染色质中发挥重要作用。介导的生物过程，包括基因调控、细胞凋亡、细胞周期调控、DNA 重组和修复。Tip60是转录因子招募的多蛋白复合体的一部分某些基因的启动子，通常使周围的组蛋白乙酰化以激活基因表情。因此，Tip60的招募参与了表观遗传基因的调控。很明显，Tip60 在转录调控中起着核心作用，但具体的组织和细胞类型尚不清楚需要Tip60才能发挥作用的发育途径和靶基因。探讨Tip60在细胞周期调控中的作用多细胞发育，本实验室已在果蝇中鉴定并克隆了人Tip60同源基因 (Dmel\Tip60)。我们已经在转基因果蝇中开发了一种系统，允许靶向和诱导野生型或显性阴性HAT缺陷Dmel\Tip60和Dmel\Tip60基因敲除的过表达选择特定的组织、细胞类型和发育阶段。使用这个系统，我们已经确定 Dmel-Tip60在发育早期对神经系统的形成是必不可少的。我们显示了损失的果蝇脑中的Dmel-Tip60可导致大量神经元丢失和致死。与我们的发现一致，其他小组已经证明了Tip60 HAT活性在转录激活中的重要作用淀粉样前体蛋白(APP)介导的细胞信号通路可能参与的靶基因在神经元发育方面。有趣的是，年轻阿尔茨海默氏症患者大脑中的Tip60水平急剧上升疾病(AD)模型小鼠在获得A？斑块之前很久就过度产生APP，神经毒性和代表疾病的行为异常。这些发现为我们的中央假设APP扰动导致内源性Tip60上调，导致 Tip60/APP和独特的Tip60染色质介导的神经元通路在两者中都是相关的发育和神经退化。为了验证这一假设，将实现以下具体目标。 Aim 1将识别参与不同神经元的Tip60表观遗传调控的靶基因发育过程和目标2将决定Tip60染色质介导的神经元的程度 APP，在体内的过度表达会影响过程和靶基因。这样的知识具有重要的以染色质为基础的治疗Tip60相关疾病的新疗法的发展。 PHS 398/2590(05/01版)第_页延续格式页原则调查员/计划总监(最后、第一、中间) 叙述：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的了解神经系统发育和神经退行性疾病。这样的知识已经对以表观遗传学为基础的新疗法发展的重要意义。 PHS 398/2590(05/01版)第_续格式页

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Microarray analysis uncovers a role for Tip60 in nervous system function and general metabolism.

DOI：
10.1371/journal.pone.0018412
发表时间：
2011-04-11
期刊：
PloS one
影响因子：
3.7
作者：
Lorbeck M;Pirooznia K;Sarthi J;Zhu X;Elefant F
通讯作者：
Elefant F

dTip60 HAT activity controls synaptic bouton expansion at the Drosophila neuromuscular junction.

DOI：
10.1371/journal.pone.0026202
发表时间：
2011
期刊：
PloS one
影响因子：
3.7
作者：
Sarthi J;Elefant F
通讯作者：
Elefant F

Targeting specific HATs for neurodegenerative disease treatment: translating basic biology to therapeutic possibilities.

DOI：
10.3389/fncel.2013.00030
发表时间：
2013
期刊：
Frontiers in cellular neuroscience
影响因子：
5.3
作者：
Pirooznia SK;Elefant F
通讯作者：
Elefant F

Disruption of Tip60 HAT mediated neural histone acetylation homeostasis is an early common event in neurodegenerative diseases.

TIP60 HAT介导的神经组蛋白乙酰化稳态的破坏是神经退行性疾病的早期常见事件。

DOI：
10.1038/s41598-020-75035-3
发表时间：
2020-10-26
期刊：
Scientific reports
影响因子：
4.6
作者：
Beaver M;Bhatnagar A;Panikker P;Zhang H;Snook R;Parmar V;Vijayakumar G;Betini N;Akhter S;Elefant F
通讯作者：
Elefant F

Tip60 HAT activity mediates APP induced lethality and apoptotic cell death in the CNS of a Drosophila Alzheimer's disease model.