Aging and brain 5-lipoxygenase

衰老与大脑 5-脂氧合酶

基本信息

批准号：
7676006
负责人：
HARI MANEV
金额：
$ 25.23万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-12-01 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7676006
关键词：
Acetylation Age Aging Agonist Alzheimer&apos s Disease Amyloid beta-Protein Precursor Amyloidosis Applications Grants Arachidonate 5-Lipoxygenase Autopsy Binding Binding Sites Biological Assay Brain Brain Pathology Brain region Cell Maturation CpG Islands Cytosine DNA Methylation Data Deoxycytidine Development Enzymes Epigenetic Process Funding Gene Expression Genes Glucocorticoids Glutamate Receptor Histone Acetylation Histone Deacetylase Histone Deacetylase Inhibitor Histones Human In Vitro Incidence Inflammatory Knock-out Laboratory Study Measures Methionine Methylation Monozygotic Twinning Monozygotic twins Mus Nerve Degeneration Neuraxis Neurons Pathology Pattern Pharmaceutical Preparations Play Predisposing Factor Prevention therapy Procedures Promoter Regions Receptor Activation Regulation Reporting Research Research Personnel Role Small Interfering RNA TFAP2A gene Techniques Testing Tg2576 Time Twin Multiple Birth Up-Regulation Work age effect aging brain base brain tissue chromatin immunoprecipitation demethylation design excitotoxicity histone modification in vitro testing in vivo mouse model neuropathology novel prevent programs promoter receptor for advanced glycation endproducts research study transcription factor valproate

项目摘要

DESCRIPTION (provided by applicant): Epigenetic mechanisms that include DNA methylation and histone modifications profoundly influence gene expression and also appear to be altered in aging. A better understanding of these mechanisms in the brain may point to novel targets for the therapy/prevention of aging-associated central nervous system pathologies. Over the last four years of funding, studies from this laboratory have established that the brain expression of 5-lipoxygenase (5-LOX), an inflammatory enzyme, increases during aging, is stimulated by glutamate receptor activation and by glucocorticoids, and might be associated with neurodegeneration, possibly in Alzheimer's disease (AD). Others have shown that 5-LOX knockout in a mouse model of Alzheimer's disease, the Tg2576 mouse, and decreases amyloidosis. Recent preliminary data indicate that neuronal 5-LOX expression increases following changes in the methylation state of CpG islands in 5-LOX promoter (e.g., by a hypomethylating drug 5-aza-2'-deoxycytidine) or after altered histone acetylation (e.g., by histone deacetylases - HDACs - inhibitors). In this proposal, we hypothesize that epigenetic mechanisms are altered in aging brain neurons and are responsible for the regulation of brain 5-LOX expression; 5-LOX expression is triggered by decreased methylation at the 5-LOX promoter and/or altered histone acetylation and methylation at the 5-LOX gene. We propose the following three specific AIMs: 1) Investigate in mice the effects of aging on a) brain DNMT1 and HDACs expression, b) brain region-specific 5-LOX promoter methylation, and c) 5-LOX-related histone acetylation and methylation; 2) In primary neuronal cultures, test the in-vitro effects of cell maturation/aging on neuronal DNMT1 and HDACs expression, 5-LOX promoter methylation, and 5-LOX-related histone acetylation and methylation; and 3) Using primary neuronal cultures, investigate the role of DNMT1 and HDACs inhibition/knockdown in 5-LOX expression. The research outlined in this grant proposal is designed to provide relevant data in support of our hypothesis that an epigenetic neuronal alteration is a putative factor that predisposes the aging brain to display an upregulated expression of the 5-LOX gene. The proposed experiments may corroborate the hypothesis that epigenetic mechanisms are involved in brain aging.

描述（由申请人提供）：包括DNA甲基化和组蛋白修饰在内的表观遗传机制深远影响基因表达，并且在衰老中似乎也有所改变。对大脑中这些机制的更好理解可能指出了治疗/预防与衰老相关的中枢神经系统病理学的新目标。在过去的四年的资金中，该实验室的研究表明，炎症酶（5-lox）的大脑表达是一种炎症酶，在衰老过程中增加，受到谷氨酸受体的激活和糖皮质激素的刺激，并且可能与神经性变性有关，并且可能与Alzheimer的神经性相关。其他人则表明，在阿尔茨海默氏病小鼠模型，TG2576小鼠的小鼠模型中，5-lox敲除，并减少淀粉样变性。最近的初步数据表明，在5-lox启动子中CpG岛的甲基化状态变化后，神经元5-LOX表达增加（例如，通过降压药5-aza-2'-脱氧胞苷）或组蛋白乙酰化改变了组蛋白乙酰化（例如，组织蛋白脱氧基酶-HDACS-HDACS-HDACS-HIDICONITORS-HINDICONS-IN-INHINIDONS-IN-INHINDONS-INHINDONS- indimins-ins）。在此提案中，我们假设表观遗传机制在衰老的脑神经元中发生了改变，并负责调节脑5-LOX表达。 5-lox表达是通过在5-lox启动子处甲基化降低和/或在5-lox基因处改变组蛋白乙酰化和甲基化触发的。我们提出以下三个特定目的：1）在小鼠中研究衰老对a）脑DNMT1和HDACS表达的影响，b）脑区域特异性5-lox启动子甲基化，c）5-lox相关的组蛋白乙酰化和甲基化； 2）在原发性神经元培养物中，测试细胞成熟/衰老对神经元DNMT1和HDACS表达，5-lox启动子甲基化以及5-LOX相关的组蛋白乙酰化和甲基化的体外作用； 3）使用原发性神经元培养物，研究DNMT1和HDAC抑制/敲低5-lox表达的作用。该赠款提案中概述的研究旨在提供相关数据，以支持我们的假设，即表观遗传神经元改变是一个假定的因素，它使大脑衰老的大脑易于显示5-lox基因的上调表达。提出的实验可能证实了表观遗传机制与大脑衰老有关的假设。