Aging and brain 5-lipoxygenase

衰老与大脑 5-脂氧合酶

• 批准号: 7495002
• 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
• 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/7495002
• 关键词: Acetylation; Age; Aging; Agonist; Alzheimer' s Disease; Amyloid beta-Protein Precursor; Amyloidosis; Appendix; 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; Histones; Human; In Vitro; Incidence; Inflammatory; Knock-out; Laboratory Study; Measures; Methionine; Methylation; Modification; Monozygotic Twinning; Monozygotic twins; Mus; Nerve Degeneration; Neuraxis; Neurons; Numbers; 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; Transcriptional Activation; Twin Multiple Birth; Up-Regulation; Work; age effect; aging brain; base; brain tissue; chromatin immunoprecipitation; demethylation; design; excitotoxicity; in vivo; inhibitor/antagonist; mouse model; neuropathology; novel; prevent; programs; promoter; receptor for advanced glycation endproducts; research study; transcription factor; valproate

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）：表观遗传机制，包括DNA甲基化和组蛋白修饰深刻影响基因表达，也似乎在衰老中发生改变。更好地了解大脑中的这些机制可能会为治疗/预防与衰老相关的中枢神经系统病变指明新的靶点。在过去四年的资助下，该实验室的研究已经确定，大脑中5-脂氧合酶（5-LOX）（一种炎症酶）的表达在衰老过程中增加，受到谷氨酸受体激活和糖皮质激素的刺激，可能与神经退行性变有关，可能与阿尔茨海默病（AD）有关。其他研究表明，在阿尔茨海默病小鼠模型Tg2576小鼠中，5-LOX敲除可以减少淀粉样变性。最近的初步数据表明，神经元5-LOX表达随着5-LOX启动子中CpG岛甲基化状态的改变（例如，通过低甲基化药物5-aza-2'-脱氧胞苷）或组蛋白乙酰化改变（例如，通过组蛋白去乙酰化酶- hdac -抑制剂）而增加。在这一提议中，我们假设表观遗传机制在衰老的大脑神经元中发生改变，并负责调节大脑5-LOX的表达；5-LOX的表达是由5-LOX启动子甲基化降低和/或5-LOX基因组蛋白乙酰化和甲基化改变触发的。我们提出以下三个具体目的：1)研究衰老对小鼠脑DNMT1和hdac表达的影响；b)脑区域特异性5-LOX启动子甲基化；c) 5-LOX相关组蛋白乙酰化和甲基化的影响；2)在原代神经元培养中，检测细胞成熟/衰老对神经元DNMT1和HDACs表达、5-LOX启动子甲基化、5-LOX相关组蛋白乙酰化和甲基化的体外影响；3)利用原代神经元培养，研究DNMT1和hdac抑制/敲低在5-LOX表达中的作用。本研究的目的是提供相关数据，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，使衰老的大脑表现出上调的5-LOX基因表达。所提出的实验可能证实了表观遗传机制参与脑衰老的假设。