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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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）：阿尔茨海默氏病（AD）易感性的潜在定量变化受多个基因、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，并且与高龄痴呆和 AD 的风险增加有关。最近在 AD 动物模型中证实了高脂肪饮食 (HFD) 对认知能力的不利影响以及脑淀粉样变性和淀粉样血管病的恶化。同样重要的是，暴露于某些有毒环境因素，例如饮用水中的砷 (As)，会引起与 AD 的病理和临床特征无法区分或一致的变化，包括：诱导 tau 过度磷酸化、淀粉样前体蛋白 (APP) 上调；增加心血管疾病；增强大脑炎症反应、小鼠高胰岛素血症以及认知和记忆缺陷。然而，目前尚不清楚 HFD 和环境暴露是否会共同增加 AD 风险和疾病进展。由饮食因素或砷暴露引起的表观遗传重编程的新兴研究和新发现强烈表明，组蛋白标记的诱导变化在整个生命过程中保留并积累以促进 AD 发病机制。因此，年龄依赖性基因-环境相互作用对于迟发性 AD (LOAD) 的发生和进展至关重要。因此，推测 HFD 和 As 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 AD 动物模型中，揭示大脑和肝脏中染色质修饰的器官特异性变化，这是由 HFD 和砷暴露的集体效应引起的，这些变化会产生全基因组致病转录活性和 2) 揭示因组蛋白变化导致的联合暴露所引起的 AD 表型特异性变化（认知表现、脑实质中的淀粉样蛋白沉积、代谢异常和血管壁重塑）修改。这一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 表型以及脂质和葡萄糖代谢的影响；目标 2：评估 AD 小鼠中 HFD 和 As 诱导的大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相关联。