Epigenetic, Neuroimaging & Behavioral Effects of Hypertension in the Aging Brain

表观遗传学、神经影像学

• 批准号: 9354285
• 负责人: GENE E ALEXANDER
• 金额: $ 45.82万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9354285
• 关键词: Affect; Age; Animals; Behavior; Behavioral; Blood Pressure; Brain; Brain region; Brain scan; Candidate Disease Gene; Cell Nucleus; Cognition; Cognitive; Cognitive aging; Communities; Control Animal; Cytochrome P450; DNA Methylation; Data; Development; Diet; Elderly; Epigenetic Process; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic Transcription; Genome; Health; High Prevalence; Hippocampus (Brain); Human; Hypertension; Hypothalamic structure; Impairment; Inbred F344 Rats; Indole-3-Carbinol; Learning; Literature; MRI Scans; Magnetic Resonance Imaging; Measures; Memory; Methods; Modeling; Modification; Molecular; Monitor; Multivariate Analysis; Mus; Neurons; Paper; Pattern; Population; Proteins; Rattus; Regression Analysis; Renin; Resolution; Rodent; Rodent Model; Structure; Synapses; Testing; Tissues; Transgenic Organisms; Work; Xenobiotics; aging brain; base; bisulfite; chromatin immunoprecipitation; cognitive ability; cognitive capacity; cognitive performance; cognitive task; differential expression; experimental study; genome-wide; gray matter; histone modification; improved; in vivo; interest; laser capture microdissection; male; methylation pattern; middle age; neuroimaging; normotensive; promoter; therapeutic target; white matter

With high prevalence in the community-dwelling elderly population, hypertension may be an important factor influencing the development and progression of cognitive aging. Although hypertension is a major health problem that has been shown to affect cognition, very little is known about its effects on the molecular status, especially the epigenetic status, of brain regions critical to cognition. However, significant literature is accumulating describing effects of selective cognitive tasks on epigenetic mechanisms in rodents. The known effect of hypertension on cognition, and the accumulating literature on the epigenetic bases of selected cognitive capacities leads to the overarching hypothesis to be tested by this project: epigenetic changes induced in a rodent model of hypertension will mirror the known relationships between cognitive tasks and epigenetic mechanisms in rodents. We focus on epigenetic mechanisms since these are major factors in the regulation of gene expression. Specifically, this project is aimed at determining epigenetic changes induced by hypertension in subregions of the brain known to be important to cognition. We will study brains from 20 normotensive controls and 20 hypertensive behaviorally characterized rats, who have also received high resolution in vivo magnetic resonance imaging (MRl) scans of brain structure and white matter integrity. Male Fischer 344 rats have the cytochrome P450 promoter (Cyp1a1) inserted to up-regulate the expression of the mouse renin (Ren2) gene, Administration of 0,15% indole-3-carbinol {I3C) to the diet of these transgenic rats activates the Cyplal promoter to induce a gradual onset of hypertension. Dependent variables will be gene expression and the major epigenetic mechanisms, DNA methylation and histone modifications, as well as measures of cognitive performance and patterns of MRl gray and white matter integrity. Defined sub-regions, of the hippocampus will be isolated by laser capture microdissection. In order to obtain sufficient starting material successive sections from the same brain will be pooled. We will assess DNA methylation on a genome wide basis by bisulfite conversion, amplification and NimbleGen arrays. PCR will be used to assess DNA methylation of specific genes based on previous findings of others and array data produced by this project. We will assess selected histone modifications by chromatin immunoprecipitation followed by PCR of selected genes. The genes we select are those previously shown to be differentially expressed in brain regions, with an emphasis on hippocampus, in association with learning and memory. We will test our major hypothesis by statistical determination of hypertension-induced epigenetic changes in our model and then compare the resulting data with epigenetic changes associated with cognitive behaviors and MRl gray and white matter integrity. We will use multivariate analyses to estimate the extent to which epigenetic variables account for cognitive status in the experimental animals.

随着社区老年人口的高患病率，高血压可能是一个重要因素 影响认知老化的发展和进展。尽管高血压是一种主要的健康 已被证明影响认知的问题，对其对分子状态的影响知之甚少， 尤其是对认知至关重要的大脑区域的表观遗传状态。然而，重要的文献是 选择性认知任务对啮齿动物表观遗传机制的累积描述效应。这个 已知的高血压对认知的影响，以及关于高血压表观遗传学基础的文献积累 选定的认知能力导致了这个项目要检验的首要假设：表观遗传学 在高血压啮齿动物模型中诱导的变化将反映认知和认知之间的已知关系 啮齿动物的任务和表观遗传机制。我们把重点放在表观遗传机制上，因为这些是主要的 基因表达调控中的因素。具体地说，这个项目旨在确定表观遗传学 高血压引起的大脑亚区的变化，已知对认知很重要。我们会 研究了20只正常血压对照组和20只具有高血压行为特征的大鼠的大脑，这些大鼠 我还接受了高分辨率的活体磁共振成像(MRL)脑部结构和白色扫描 物质上的正直。雄性Fischer 344大鼠插入细胞色素P450启动子(Cyp1a1)上调 日粮中添加0，15%吲哚-3-甲醇对小鼠肾素(Ren2)基因表达的影响 这些转基因大鼠激活Cyplal启动子，导致逐渐发生高血压。依赖 变量将是基因表达和主要的表观遗传机制，DNA甲基化和组蛋白 修改，以及测量认知能力和MRL灰质和白质的模式 正直。将通过激光捕获显微解剖来分离海马区的已定义的亚区。按顺序 为了获得足够的起始材料，来自同一大脑的连续切片将被汇集在一起。我们将评估 通过亚硫酸氢盐转化、扩增和NimbleGen阵列在全基因组基础上进行DNA甲基化。聚合酶链反应 将用于根据其他人和阵列之前的发现评估特定基因的DNA甲基化 由该项目产生的数据。我们将通过染色质评估选定的组蛋白修饰 免疫沉淀，然后选择基因的聚合酶链式反应。我们选择的基因是之前显示的那些 在大脑区域差异表达，重点是海马体，与 学习和记忆。我们将通过高血压诱发的统计数据来检验我们的主要假设。 我们模型中的表观遗传变化，然后将结果数据与相关表观遗传变化进行比较 有认知行为和MRL灰质和白质完整性。我们将使用多变量分析来 估计表观遗传变量在多大程度上影响实验动物的认知状态。