Genome wide analysis of LXR binding - metabolic and epigenetic regulation in AD

LXR 结合的全基因组分析 - AD 中的代谢和表观遗传调控

基本信息

批准号：
8721296
负责人：
ILIYA LEFTEROV
金额：
$ 47.5万
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 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8721296
关键词：
Activities of Daily Living Address Age Agonist Alzheimer&apos s Disease Amyloid Behavior Behavioral Binding Sites Biochemical Biochemical Pathway Brain Cations Cholesterol Chromatin Cognitive Complex Coupled DNA Data Data Set Dementia Deposition Development Diet Dietary Practices Disease Disease Progression Down-Regulation Elderly Environmental Risk Factor Epigenetic Process Exposure to Fatty acid glycerol esters Future Gene Proteins Gene Targeting Generations Genes Genome Genotype Goals Health High-Throughput Nucleotide Sequencing Human Hyperinsulinism Impaired cognition Inflammatory Insulin Resistance Knowledge Late Onset Alzheimer Disease Life Life Style Lipoproteins Liver Location Massive Parallel Sequencing Mediating Memory impairment Metabolic Metabolic Pathway Modification Mus Nuclear Nutritional Obesity Organ Pathogenesis Pathology Pathway Analysis Patients Performance Peripheral Persons Pharmacological Treatment Phenotype Phospholipids Play Predisposition Proteins Reaction Receptor Activation Regulation Reporting Reproduction Research Resolution Risk Role Signal Transduction Skin Aging Stimulus Testing Therapeutic Effect Tissues Transgenic Mice Up-Regulation Variant age related base chromatin immunoprecipitation chromatin modification cognitive function disease phenotype gene environment interaction gene function genome wide association study genome-wide glucose metabolism histone modification hypercholesterolemia in vivo insulin secretion lipid metabolism long term memory middle age mouse model novel therapeutics receptor receptor binding receptor function research study response trait transcription factor

项目摘要

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common form of dementia with more than 5.5 million patients in the USA, a number that will quadruple by 2047. The disease can be characterized as an accelerated loss of cognitive functioning to such an extent that it interferes drastically with a person's daily life and activities. AD is a complex trait in that underlying quantitative variation in susceptibility is controlled by multiple genes and environmental factors. Importantly, some of these environmental and metabolic stimuli, like hypercholesterolemia, obesity, hyperinsulinemia and insulin resistance, which follow certain dietary patterns and lifestyle, are associated with increased risk of dementia and AD at advanced age, only if confronted in midlife. In this respect the epigenetic reprogramming by dietary agents, which change histone modifications and are retained throughout the life, should be considered highly relevant to AD pathogenesis, supporting the idea of age dependent gene-environment interactions as critical for the development and progression of late onset AD (LOAD). The metabolic pathways of cholesterol and phospholipid transport in the periphery and CNS, as well as some rate limiting steps of insulin secretion, are controlled by oxysterol-sensing transcription factors nuclear liver X receptors (LXRs) - LXR1 and LXR2, through the expression level of their responsive genes. We hypothesize that in the context of AD the response to high fat diet (HFD) is mediated by epigenetic chromatin modification and LXR binding to DNA and is ultimately realized by tissue and organ-selective transcriptional activity. The goal of this proposal has two major aspects: Aim 1. Using second generation high throughput sequencing to assess changes in chromatin modifications induced by nutritional signals and their role in the development and progression of cognitive performance and AD pathology. Aim 2. To reveal genome-wide changes in LXR binding caused by HFD and thus to identify LXR targets whose transcriptional up- or down-regulation has a role in the development and progression of AD-like phenotype in model mice.

描述（由申请人提供）：阿尔茨海默病 (AD) 是最常见的痴呆症，在美国有超过 550 万患者，到 2047 年这个数字将增加四倍。该疾病的特点是认知功能加速丧失，严重干扰一个人的日常生活和活动。 AD 是一种复杂的性状，易感性的潜在数量变化受多个基因和环境因素控制。重要的是，其中一些环境和代谢刺激，如高胆固醇血症、肥胖、高胰岛素血症和胰岛素抵抗，遵循某些饮食模式和生活方式，与高龄痴呆和阿尔茨海默氏症的风险增加有关，只有在中年时才会出现这种情况。在这方面，膳食制剂的表观遗传重编程改变了组蛋白修饰并在整个生命中保留，应被认为与 AD 发病机制高度相关，支持年龄依赖性基因-环境相互作用对于晚发性痴呆的发生和进展至关重要的观点AD（负载）。外周和中枢神经系统中胆固醇和磷脂转运的代谢途径，以及胰岛素分泌的一些限速步骤，由氧甾醇敏感转录因子核肝 X 受体 (LXR) - LXR1 和 LXR2 控制，通过他们的反应基因。我们假设，在 AD 背景下，对高脂肪饮食 (HFD) 的反应是通过表观遗传染色质修饰和 LXR 与 DNA 的结合介导的，并最终通过组织和器官选择性转录活性来实现。该提案的目标有两个主要方面：目标 1. 使用第二代高通量测序来评估营养信号诱导的染色质修饰的变化及其在认知表现和 AD 病理学的发展和进展中的作用。目标 2. 揭示 HFD 引起的 LXR 结合的全基因组变化，从而鉴定其转录上调或下调在模型小鼠 AD 样表型的发生和进展中发挥作用的 LXR 靶点。