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:
  • 金额:
    $ 47.5万
  • 依托单位:
  • 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

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(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年这个数字将翻两番。这种疾病的特征可以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是一个复杂的性状,因为易感性的潜在数量变异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,遵循一定的饮食模式和生活方式,只有在中年遇到时,才会与老年痴呆和AD的风险增加相关。在这方面,饮食因素的表观遗传重编程改变了组蛋白的修饰,并在整个生命周期中保持不变,应该被认为与AD的发病机制高度相关,支持年龄相关的基因-环境相互作用对迟发性AD(LOAD)的发生和发展至关重要的观点。胆固醇和磷脂在外周和中枢神经系统的代谢途径,以及胰岛素分泌的一些限速步骤,都是由氧固醇敏感转录因子核肝X受体(LXRs)-LXR1和LXR2通过其反应基因的表达水平来控制的。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的染色质修饰和LXR与DNA结合介导的,最终通过组织和器官选择性转录活动实现。该方案的目标有两个主要方面:目的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病理的发展和进展中的作用。目的2.揭示HFD引起的LXR结合的全基因组变化,从而确定其转录上调或下调在模型小鼠AD样表型的发生和发展中起作用的LXR靶点。

项目成果

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ILIYA LEFTEROV其他文献

ILIYA LEFTEROV的其他文献

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{{ truncateString('ILIYA LEFTEROV', 18)}}的其他基金

Genome Wide Analysis LXR Binding-Metabolic and Epigenetic Regulation in AD
AD 中的 LXR 结合代谢和表观遗传调控全基因组分析
  • 批准号:
    9134980
  • 财政年份:
    2016
  • 资助金额:
    $ 47.5万
  • 项目类别:
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
  • 批准号:
    8105931
  • 财政年份:
    2012
  • 资助金额:
    $ 47.5万
  • 项目类别:
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
  • 批准号:
    8534011
  • 财政年份:
    2012
  • 资助金额:
    $ 47.5万
  • 项目类别:
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
  • 批准号:
    8850762
  • 财政年份:
    2012
  • 资助金额:
    $ 47.5万
  • 项目类别:
Screening for LXR agonists-inhibitors of brain amyloidosis and inflammation
筛选 LXR 激动剂 - 脑淀粉样变性和炎症抑制剂
  • 批准号:
    7449780
  • 财政年份:
    2008
  • 资助金额:
    $ 47.5万
  • 项目类别:
Screening for LXR agonists-inhibitors of brain amyloidosis and inflammation
筛选 LXR 激动剂 - 脑淀粉样变性和炎症抑制剂
  • 批准号:
    7613357
  • 财政年份:
    2008
  • 资助金额:
    $ 47.5万
  • 项目类别:
ABCA1 knock-in mouse model to study molecular pathology of Alzheimer's Disease
ABCA1敲入小鼠模型研究阿尔茨海默病的分子病理学
  • 批准号:
    7135415
  • 财政年份:
    2006
  • 资助金额:
    $ 47.5万
  • 项目类别:
ABCA1 knock-in mouse model to study molecular pathology of Alzheimer's Disease
ABCA1敲入小鼠模型研究阿尔茨海默病的分子病理学
  • 批准号:
    7268704
  • 财政年份:
    2006
  • 资助金额:
    $ 47.5万
  • 项目类别:
Therapeutic potential-LXR ligands in Alzheimer's Disease
LXR配体在阿尔茨海默病中的治疗潜力
  • 批准号:
    6828508
  • 财政年份:
    2004
  • 资助金额:
    $ 47.5万
  • 项目类别:
Therapeutic potential-LXR ligands in Alzheimer's Disease
LXR配体在阿尔茨海默病中的治疗潜力
  • 批准号:
    6942235
  • 财政年份:
    2004
  • 资助金额:
    $ 47.5万
  • 项目类别:

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