Molecular markers of chronic stress vulnerability/resilience

慢性应激脆弱性/恢复力的分子标记

• 批准号: 7213600
• 负责人: Eva E Redei
• 金额: $ 23.52万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-11 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7213600
• 关键词: Molecular; markers; chronic; stress; vulnerability

DESCRIPTION (provided by applicant): Stress initiates a cascade of biochemical events in the brain and peripheral systems that enable the organism to cope with novel and challenging situations. However, the cumulative effects of chronic stress states negatively affects most physiologic systems because the target cells are exposed to the stress mediators over a long period of time. Human findings, pointing to a linkage between chronic stress and anxiety disorders, depression and cognitive impairments, have been extensively supported by behavioral observations in rodents. The physiological and behavioral consequences of chronic or prolonged stress depend on genetic and environmental mediators of the individual's vulnerability. The molecular mechanisms of vulnerability or resilience are not known despite the large number of studies investigating stress. This proposal aims to determine the molecular markers of sensitivity and resilience to chronic stress as a first step towards the identification of stress mediators. The aims of this proposal are: Specific Aim 1) Determine the behavioral consequences of chronic restraint stress, during and after the cessation of a chronic restrain stress (CRS) paradigm in four different inbred strains of rats. These inbred strains, the Wistar Kyoto (WKY), Fisher 344 (F344), Brown Norway (BN) and Lewis (LEW), are chosen to represent distinctive susceptibility and/or resilience to chronic stress. The elevated plus-maze (EPM) test will be employed to assess the effect of chronic stress on anxiety-related behavioral responses. Specific Aim 2) Using a hypothesis-generating, unbiased approach, the Affimetrix DMA microarray analysis, we will examine the gene expression profile changes in two brain areas, the amygdale and the hippocampus, and blood of male animals from the four inbred strains in response to CRS. Microarray analysis will be carried out on tissues obtained from animals exposed to: i) No stress, which will serve to determine the baseline gene expression ii.) 14 days of the CRS paradigm, which will inform us on the molecular markers of stress responsivity, and iii.) 10 days after the cessation of CRS to determine markers of post-stress responsivity. By employing microarray analyses of RNA isolated form two brain regions highly relevant to anxiety and stress and from blood, we will determine the common profiles of gene expression in these tissues during and after chronic stressor exposure. Specific Aim 3. Confirm the most promising candidate marker genes by quantitative real-time RT-PCR. This exploratory study will identify genes that are altered solely or concomitantly in specific brain regions or blood in response to chronic stress. These scenarios would allow us to identify candidate markers of chronic stress from the blood representing an accessible source of genetic material in humans.

描述(申请人提供)：压力在大脑和外周系统中启动一系列生化事件，使有机体能够应对新的和具有挑战性的情况。然而，慢性应激状态的累积效应会对大多数生理系统产生负面影响，因为靶细胞长期暴露在应激介质中。人类的发现指出了慢性压力与焦虑症、抑郁症和认知障碍之间的联系，并得到了对啮齿动物的行为观察的广泛支持。慢性或长期应激的生理和行为后果取决于遗传和环境因素对个体脆弱性的影响。尽管有大量研究对压力进行了研究，但脆弱性或弹性的分子机制尚不清楚。这项建议旨在确定对慢性应激的敏感性和恢复力的分子标记，作为识别应激介质的第一步。这项建议的目的是：1)在四个不同的近交系大鼠中，确定慢性束缚应激在慢性束缚应激(CRS)范式停止期间和之后的行为后果。这些近交系，Wistar京都(WKY)，费舍尔344(F344)，棕色挪威(BN)和刘易斯(LEW)，被选为代表对慢性压力的独特敏感性和/或韧性。高架加迷宫(EPM)测试将用于评估慢性应激对焦虑相关行为反应的影响。具体目的2)利用一种假设生成、无偏倚的方法，Affimetrix DMA微阵列分析，我们将检测四个近交系雄性动物对CRS反应的两个大脑区域，杏仁核和海马体，以及血液中基因表达谱的变化。将对从以下情况下暴露的动物的组织进行微阵列分析：i)无应激，这将用于确定基线基因表达；ii)CRS范例的14天，它将告知我们应激响应性的分子标志物；以及iii)CRS停止10天后，以确定应激后响应性的标志物。通过对从两个与焦虑和压力高度相关的大脑区域和血液中分离出的RNA进行微阵列分析，我们将确定在长期应激源暴露期间和之后这些组织中基因表达的共同特征。具体目的3.用实时定量RT-PCR方法确定最有希望的候选标记基因。这项探索性研究将确定在特定大脑区域或血液中单独或伴随改变的基因，以应对慢性压力。这些情景将使我们能够从血液中识别慢性应激的候选标记，代表人类遗传物质的可获得来源。