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

主要调查员/计划总监（最后，第一，中间）Elefant，Felice 摘要：TIP60和APP神经元开发 TIP60是一种关键的组蛋白乙酰转移酶（HAT）酶，在潜水染色质中起重要作用介导的生物过程，包括基因调节，凋亡，细胞周期调节，DNA 重组和修复。 TIP60是由转录因子募集到的多蛋白络合物的一部分某些基因的启动子，其中通常乙酰酸酯周围的组蛋白激活基因表达。这，TIP60募集参与表观遗传基因调节。虽然有证据表明TIP60 在转录控制中起着核心作用，在组织和细胞类型特异性方面尚不清楚需要TIP60发挥作用的发育途径和目标基因。调查tip60在多细胞发展，我们的实验室已经鉴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，该系统允许有针对性和诱导性野生型或主要负帽的过表达DMEL \ TIP60和DMEL \ TIP60敲低选择的特定组织，细胞类型和发育阶段。使用此系统，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。我们表明损失蝇脑中的DMEL \ TIP60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TIP60帽子活动在转录激活中的重要作用通过淀粉样蛋白前体蛋白（APP）介导的细胞信号传导途径的靶基因有趣的是，TIP60水平在年轻的阿尔茨海默氏症大脑中急剧增加疾病（AD）模型小鼠在获得A斑，神经毒性和神经毒性和行为异常代表该疾病。这些发现为我们的中心提供了基础假设应用程序扰动会导致内源性tip60上调 TIP60/APP和独家TIP60染色质介导的神经元途径都相关发展和神经变性。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的表观遗传调节的靶基因基因发育过程和目标2将确定TIP60染色质介导的神经元的程度过程和靶基因受体内过度表达的影响。这样的知识很重要在TIP60相关疾病中基于新型染色质治疗的发展的意义。 PHS 398/2590（修订版05/01）页_____持续格式页面主要调查员/计划总监（最后，第一，中间）Elefant，Felice 叙述：我们破译TIP60和APP在神经元发展中的作用的目标应深刻地增强我们的了解神经系统发育和神经退行性疾病。这样的知识有对新型表观遗传治疗的发展的重要意义。 PHS 398/2590（Rev. 05/01）页_____连续格式页面

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

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

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

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