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

描述（由申请人提供）：阿尔茨海默病（AD）是最常见的痴呆症形式，在美国有超过550万患者，到2047年这一数字将翻两番。这种疾病的特点是认知功能的加速丧失，以至于严重干扰了一个人的日常生活和活动。AD是一种复杂的性状，因为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，这些环境和代谢刺激中的一些，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，与老年痴呆症和AD的风险增加有关，只有在中年时才能遇到。在这方面，饮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过程中保留，应被认为与AD发病机制高度相关，支持年龄依赖性基因-环境相互作用对晚发型AD（LOAD）的发展和进展至关重要的观点。外周和CNS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，通过其响应基因的表达水平，由氧固醇敏感转录因子核肝X受体（LXR）-LXR 1和LXR 2控制。我们假设，在AD的背景下，对高脂饮食（HFD）的反应是由表观遗传染色质修饰和LXR结合DNA介导的，并最终通过组织和器官选择性转录活性实现。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评估营养信号诱导的染色质修饰的变化及其在认知能力和AD病理学发展和进展中的作用。目标二。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起作用的LXR靶点。

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.