Social Regulation of Gene Expression

基因表达的社会调节

基本信息

  • 批准号:
    8423751
  • 负责人:
  • 金额:
    $ 34.28万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-03-01 至 2015-02-28
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Research has repeatedly shown that a lack of social ties increases risk for poor health. Recent research has demonstrated that poor mental and physical health outcomes are distally associated with social isolation, are more proximally associated with perceived social isolation, and are not explicable in terms of differences in health behaviors. Recent studies have identified alterations in hypothalamic-pituitary-adrenal (HPA) axis regulation of inflammatory biology in leukocytes as a potential mechanism of isolation-related health risks. Individuals reporting chronically high levels of subjective social isolation have shown a heightened rise in morning cortisol levels (Adams et al. 2006), and alterations in genome-wide transcription of glucocorticoid target genes and NF-:B target genes (Cole et al. 2007). These isolation-related alterations in leukocyte biology might stem from a functional desensitization of the glucocorticoid receptor (GR) in isolated people (Cole 2008), which in turn, is reciprocally related to NF-:B expression, a key factor in regulation of cellular responses to infection, cancer, and inflammation. Impaired transcription of glucocorticoid response genes and increased activity of pro-inflammatory transcription control pathways provide a functional genomic explanation for elevated risk of inflammatory disease in individuals who experience chronically high levels of perceived social isolation. Initial genomics analyses tested a relatively small sample and provided preliminary support for this hypothesis. This revised application seeks to extend those initial findings by (1) expanding the range of genomic analyses, (2) identifying the specific aspect of glucocorticoid-mediated transcriptional control driving those effects, (3) determining the plausibility of a causal role for subjective social isolation in predicting transcriptional control in longitudinal studies, and (4) establishing an animal model of subjective social isolation that can provide a platform for experimental studies. Utilizing participants from the Chicago Health, Aging and Social Relations longitudinal study, a population-based sample of middle-aged and older adults, we investigate whether transcriptional alterations occur only in those who show chronically high levels of subjective isolation, or whether similar effects occur even at minimal or variable levels of subjective isolation. Differential expression of GR and/or NF-:B proteins, and/or post-translational modifications of the GR (e.g., GR phosphorylation) will be examined as potential molecular mechanisms of altered glucocorticoid transcriptional control. The plausibility of a causal role for social isolation will be evaluated by examining the extent to which naturally occurring changes in subjective isolation over a two-year period predict changes in transcriptional control. Finally, a non-human primate model will be evaluated by conducting social behavioral assays to distinguish among and determine stability of "sociability" phenotypes in adult male rhesus monkeys, and biological assays will be done to determine relationships between social phenotypes and measures of HPA activity, GR- mediated signal transduction, and genome-wide transcriptional profiles.
描述(由申请人提供):研究一再表明,缺乏社会联系会增加健康状况不佳的风险。最近的研究表明,不良的心理和身体健康结果与社会隔离有着远距离的联系,与感知的社会隔离有着更近的联系,并且无法用健康行为的差异来解释。最近的研究已经确定了白细胞中炎症生物学的下丘脑-垂体-肾上腺(HPA)轴调节的改变是与隔离相关的健康风险的潜在机制。报告长期高度主观社会隔离的个体显示早晨皮质醇水平升高(亚当斯等人,2006),糖皮质激素靶基因和NF-:B靶基因的全基因组转录发生改变(科尔等人,2007)。这些与隔离相关的白细胞生物学改变可能源于隔离人群中糖皮质激素受体(GR)的功能性脱敏(科尔2008),而这又与NF-:B表达密切相关,NF-:B是调节细胞对感染、癌症和炎症反应的关键因子。糖皮质激素反应基因转录受损和促炎转录控制途径活性增加为长期高水平感知社会隔离的个体中炎性疾病风险升高提供了功能基因组学解释。最初的基因组学分析测试了相对较小的样本,并为这一假设提供了初步支持。该修订后的申请旨在通过以下方式扩展这些初步发现:(1)扩大基因组分析的范围,(2)确定糖皮质激素介导的转录控制驱动这些效应的具体方面,(3)确定主观社会隔离在纵向研究中预测转录控制的因果作用的可能性,(4)建立主观社会隔离的动物模型,为实验研究提供平台。利用参与者从芝加哥健康,老龄化和社会关系纵向研究,一个基于人口的样本的中年和老年人,我们调查是否转录改变只发生在那些谁表现出长期高水平的主观隔离,或是否发生类似的影响,即使在最低或可变水平的主观隔离。GR和/或NF-:B蛋白的差异表达,和/或GR的翻译后修饰(例如,GR磷酸化)将作为改变糖皮质激素转录控制的潜在分子机制进行检查。社会隔离的因果作用的可解释性将通过检查在何种程度上自然发生的变化,主观隔离超过两年的时间预测转录控制的变化进行评估。最后,将通过进行社会行为测定来评价非人灵长类动物模型,以区分成年雄性恒河猴中的“社会性”表型并确定其稳定性,并且将进行生物测定以确定社会表型与HPA活性、GR介导的信号转导和全基因组转录谱的测量之间的关系。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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John T. Cacioppo其他文献

#117 Depression symptom scores predict altered pro-inflammatory cytokine release and glucocorticoid resistance in nondepressed individuals
  • DOI:
    10.1016/j.bbi.2005.10.124
  • 发表时间:
    2005-07-01
  • 期刊:
  • 影响因子:
  • 作者:
    Lara A. Regis;Christopher G. Engeland;Jos A. Bosch;John T. Cacioppo;Phillip T. Marucha
  • 通讯作者:
    Phillip T. Marucha
Self-statements and self-evaluations: A cognitive-response analysis of heterosocial anxiety
自我陈述与自我评价:对异性交往焦虑的认知反应分析
  • DOI:
    10.1007/bf01185965
  • 发表时间:
    1979-09-01
  • 期刊:
  • 影响因子:
    2.000
  • 作者:
    John T. Cacioppo;Carol R. Glass;Thomas V. Merluzzi
  • 通讯作者:
    Thomas V. Merluzzi
#10 Selective mobilization of the inflammatory CD14dim-CD16bright monocytes during acute psychological stress
  • DOI:
    10.1016/j.bbi.2005.10.016
  • 发表时间:
    2005-07-01
  • 期刊:
  • 影响因子:
  • 作者:
    Jos A. Bosch;Gary G. Berntson;John T. Cacioppo;Philip T. Marucha
  • 通讯作者:
    Philip T. Marucha

John T. Cacioppo的其他文献

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{{ truncateString('John T. Cacioppo', 18)}}的其他基金

Social Regulation of Gene Expression - Supplement
基因表达的社会调节 - 补充
  • 批准号:
    9442027
  • 财政年份:
    2017
  • 资助金额:
    $ 34.28万
  • 项目类别:
Social Regulation of Gene Expression
基因表达的社会调节
  • 批准号:
    9233884
  • 财政年份:
    2017
  • 资助金额:
    $ 34.28万
  • 项目类别:
Social Regulation of Gene Expression
基因表达的社会调节
  • 批准号:
    8768616
  • 财政年份:
    2010
  • 资助金额:
    $ 34.28万
  • 项目类别:
Social Regulation of Gene Expression
基因表达的社会调节
  • 批准号:
    8223259
  • 财政年份:
    2010
  • 资助金额:
    $ 34.28万
  • 项目类别:
Social Regulation of Gene Expression
基因表达的社会调节
  • 批准号:
    8913329
  • 财政年份:
    2010
  • 资助金额:
    $ 34.28万
  • 项目类别:
Social Regulation of Gene Expression
基因表达的社会调节
  • 批准号:
    8643186
  • 财政年份:
    2010
  • 资助金额:
    $ 34.28万
  • 项目类别:
Social Regulation of Gene Expression
基因表达的社会调节
  • 批准号:
    7786456
  • 财政年份:
    2010
  • 资助金额:
    $ 34.28万
  • 项目类别:
Social Regulation of Gene Expression
基因表达的社会调节
  • 批准号:
    8032481
  • 财政年份:
    2010
  • 资助金额:
    $ 34.28万
  • 项目类别:
The Integrative Social Relations, Health and Aging Project
综合社会关系、健康和老龄化项目
  • 批准号:
    7934252
  • 财政年份:
    2009
  • 资助金额:
    $ 34.28万
  • 项目类别:
The Integrative Social Relations, Health and Aging Project
综合社会关系、健康和老龄化项目
  • 批准号:
    7934249
  • 财政年份:
    2009
  • 资助金额:
    $ 34.28万
  • 项目类别:

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