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）：阿尔茨海默病（AD）易感性的潜在定量变化受多种基因、环境因素和代谢信号控制。重要的是，一些代谢刺激，如高胆固醇血症、肥胖、高胰岛素血症和胰岛素抵抗，遵循一定的饮食模式和生活方式，并与老年痴呆症和阿尔茨海默病的风险增加有关。高脂肪饮食（HFD）对认知能力和大脑淀粉样变性和淀粉样血管病的恶化的有害影响最近在AD的动物模型中得到了证实。同样重要的是，暴露于一些有毒的环境因素，如饮用水砷（as），会引起与AD的病理和临床特征难以区分的变化，包括：诱导tau过度磷酸化，淀粉样前体蛋白（APP）上调；心血管疾病增加；脑炎症反应增强，小鼠高胰岛素血症，认知和记忆缺陷。然而，HFD和环境暴露是否会增加AD风险和疾病进展，目前还完全未知。饮食或砷暴露导致的表观遗传重编程的新研究和新发现强烈表明，组蛋白标记的诱导变化会在整个生命中保留并积累，从而促进AD的发病。因此，年龄依赖性基因-环境相互作用对晚发型AD （LOAD）的发生和进展至关重要。因此，假设HFD和As对表观遗传染色质修饰的综合影响导致致病性组织和器官选择性转录活性，从而增加发生、加速或加重AD表型的风险。拟议研究的目标是：1)在一个完善的阿尔茨海默病动物模型中，揭示由HFD和As暴露的集体效应引起的脑和肝脏染色质修饰的器官特异性变化，产生全基因组致病性转录活性；2)揭示阿尔茨海默病表型特异性变化(认知能力，脑实质淀粉样蛋白沉积，代谢异常和血管壁重塑)由组蛋白修饰变化引起的联合暴露引起。该目标将通过实现以下具体目标来实现：目标1：揭示集体暴露于HFD和As对AD表型和脂质和葡萄糖代谢的影响；目的2：评估HFD和As在AD小鼠中诱导的脑和肝脏染色质修饰的变化，并将表观基因组的特定变化与行为缺陷和脑淀粉样变性联系起来。