Epigenomic impact of diet and toxicant exposure in Alzheimers disease etiology

饮食和有毒物质暴露对阿尔茨海默病病因的表观基因组影响

• 批准号: 8538388
• 负责人: Aaron Barchowsky
• 金额: $ 23.34万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8538388
• 关键词: Acetylation; Address; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein Precursor; Amyloid deposition; Amyloidosis; Animal Model; Arsenic; Behavioral; Biochemical Pathway; Blood Vessels; Brain; Cardiovascular Diseases; Cardiovascular system; Cerebrum; Cessation of life; Cholesterol; Chromatin; Clinical; Cognitive; Cognitive deficits; Coupled; DNA; Data Set; Dementia; Development; Diagnostic; Diet; Dietary Practices; Disease; Disease Progression; Down-Regulation; Elderly; Environmental Exposure; Environmental Risk Factor; Epigenetic Process; Etiology; Exposure to; Fatty acid glycerol esters; Gene Proteins; Genes; Goals; Health; Histones; Human; Hyperinsulinism; Impaired cognition; Inflammatory; Insulin Resistance; Knowledge; Late Onset Alzheimer Disease; Life; Life Style; Liver; Location; Memory impairment; Metabolic; Methylation; Molecular; Mus; Neurofibrillary Tangles; Nutritional; Obesity; Organ; Pathogenesis; Pathology; Pathway Analysis; Patients; Performance; Peripheral; Persons; Phenotype; Play; Predisposition; Protein Precursors; Proteins; Reaction; Research; Resolution; Risk; Role; Senile Plaques; Signal Transduction; Stimulus; Testing; Tissues; Toxicant exposure; Transgenic Animals; Translating; Up-Regulation; Variant; age related; base; chromatin modification; cognitive function; disease phenotype; drinking water; epigenome; epigenomics; extracellular; feeding; gene environment interaction; genome-wide; glucose metabolism; histone modification; hypercholesterolemia; lipid metabolism; novel; novel therapeutics; tau Proteins

DESCRIPTION (provided by applicant): The underlying quantitative variation in susceptibility to develop Alzheimer's disease (AD) is controlled by multiple genes, environmental factors, and metabolic signals. Importantly, some metabolic stimuli, like hypercholesterolemia, obesity, hyperinsulinemia and insulin resistance, follow certain dietary patterns and lifestyle, and are associated with increased risk of dementia and AD at advanced age. The detrimental effects of high fat diet (HFD) on cognitive performance and exacerbation of cerebral amyloidosis and amyloid angiopathy has been recently demonstrated in an animal model of AD. Equally important, exposure to some toxic environmental factors, such as drinking water arsenic (As), induces changes that are indistinguishable from, or coincide with pathological and clinical features of AD including: induced tau hyperphosphorylation, upregulation of amyloid precursor protein (APP); increased cardiovascular disease; enhanced brain inflammatory reactions, hyperinsulinemia in mice, and cognitive and memory deficits. It is completely unknown, however, whether HFD and environmental exposures combine to increase AD risk and disease progression. Emerging research and novel findings of epigenetic reprogramming inflicted by dietary agents or As exposure strongly suggest that induced changes in histone marks are retained throughout the life and accumulate to promote AD pathogenesis. Thus age dependent gene-environment interactions are critical for the development and progression of late onset AD (LOAD). It is therefore hypothesized that the combined impact of HFD and As on epigenetic chromatin modifications results in pathogenic tissue and organ-selective transcriptional activity that translates into increased risk of developing, accelerating or aggravating AD phenotypes. The objectives of the proposed research are: 1) In a well-established animal model for AD, to reveal organ specific changes in chromatin modifications in brain and liver, instigated by the collective effect of HFD and As exposure that produce genome wide pathogenic transcriptional activity, and 2) To reveal changes specific for AD phenotype (cognitive performance, amyloid deposition in brain parenchyma, metabolic abnormality and blood vessel wall remodeling) caused by combined exposures that result from identified changes in histone modifications. This goal will be achieved by accomplishing the following Specific Aims: Aim 1: To reveal the consequences of collective exposure to HFD and As on AD phenotype and lipid and glucose metabolism; and Aim 2: To assess changes in chromatin modifications in brain and liver induced by HFD and As in AD mice and to correlate specific changes in the epigenome to behavioral deficits and brain amyloidosis.

描述（由申请人提供）：开发阿尔茨海默氏病（AD）的易感性的基本定量变化受多种基因，环境因素和代谢信号的控制。重要的是，某些代谢刺激，例如高胆固醇血症，肥胖症，高胰岛素血症和胰岛素抵抗，遵循某些饮食模式和生活方式，并且与高龄痴呆症和AD的风险增加有关。高脂肪饮食（HFD）对脑淀粉样变性和淀粉样血管病的认知性能和加剧的影响，最近在AD的动物模型中证明了高脂肪的影响。同样重要的是，暴露于某些有毒环境因素（例如饮用水砷）（AS），引起与AD的病理和临床特征相吻合或与之一致的变化，包括：诱导的TAU高磷酸化，淀粉样蛋白前体蛋白（APP）的淀粉样前体前体蛋白质上调；心血管疾病增加；增强的脑炎症反应，小鼠高胰岛素血症以及认知和记忆缺陷。但是，HFD和环境暴露是否相结合以增加AD风险和疾病进展，这是完全未知的。饮食剂或暴露的新兴研究和新颖的表观遗传重编程发现强烈表明，在整个生命中保留了诱导的组蛋白标记变化并积累以促进AD发病机理。因此，依赖年龄依赖的基因环境相互作用对于晚期发作AD的发展和进展至关重要（负载）。因此，假设HFD和对表观遗传染色质修饰的综合影响会导致致病性组织和器官选择性转录活性，从而转化为增加，加速或加剧AD表型的风险增加。 The objectives of the proposed research are: 1) In a well-established animal model for AD, to reveal organ specific changes in chromatin modifications in brain and liver, instigated by the collective effect of HFD and As exposure that produce genome wide pathogenic transcriptional activity, and 2) To reveal changes specific for AD phenotype (cognitive performance, amyloid deposition in brain parenchyma, metabolic abnormality and blood vessel wall remodeling)由鉴定出组蛋白修饰变化导致的组合暴露引起。实现以下特定目标将实现此目标：目标1：揭示集体暴露于HFD以及AD表型以及脂质和脂肪代谢的后果；和目标2：评估HFD和AD小鼠诱导的大脑和肝脏中染色质修饰的变化，并将表观基因组的特定变化与行为缺陷和脑淀粉样变性相关。