GENETICS, ENDOCRINOLOGY AND PTSD RISK IN POPULATION

人口中的遗传学、内分泌学和创伤后应激障碍风险

• 批准号: 7605325
• 负责人: RACHEL YEHUDA
• 金额: $ 3.28万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7605325
• 关键词: Accounting; Area; Biological Process; Clinical; Complex; Computer Retrieval of Information on Scientific Projects Database; DNA Methylation; Development; Disease; Endocrinology; Epigenetic Process; Event; Failure; Functional disorder; Funding; Genes; Genetic; Genetic Polymorphism; Genotype; Glucocorticoid Receptor; Glucocorticoids; Grant; Homeostasis; Hormones; Hydrocortisone; Individual Differences; Institution; Investigation; Lymphocyte; Measures; Mental Health; Modeling; Molecular; Molecular Genetics; Molecular Profiling; Neurosecretory Systems; New York; Parents; Persons; Phenotype; Physiological; Polymerase Chain Reaction; Population; Post-Traumatic Stress Disorders; Promoter Regions; Purpose; Range; Recruitment Activity; Research; Research Personnel; Resistance; Resources; Risk; Risk Factors; Role; Sampling; Severities; Signal Transduction; Site; Source; Stress; System; Techniques; Time; Tissues; Trauma; United States National Institutes of Health; Woman; base; cohort; environmental stressor; experience; gene environment interaction; genetic risk factor; intergenerational; men; metropolitan; neurotransmission; programs; promoter; response; transmission process

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This proposal seeks to examine gene-environment interactions that contribute to the development of PTSD in 200 persons selected from a well-characterized sample of 2750 men and women in the New York metropolitan area, exposed to the World Trade Center attacks. This cohort was recruited six months after September 11, has been followed longitudinally for the purpose of determining mental health consequences resulting from this event, and is sufficiently large enough to undertake a comprehensive investigation of risk factors for this disorder. We will examine clinical and neuroendocrine measures previously hypothesized or demonstrated to be associated with risk for PTSD, related to alterations in cortisol signaling. Since genetic factors contribute to the function of this biological system, we will examine polymorphisms of several genes related to glucocorticoid activity, as well as peptidergic and monoaminergic neurotransmission implicated in PTSD pathophysiology. To determine other relevant genes, we will examine expression profiles using microarray techniques and quantitative polymerase chain reaction. The subset of genes that are validated will also be genotyped for association with PTSD. Additionally, based on our recent evidence for non-genetic intergenerational transmission of PTSD and cortisol alterations associated with PTSD (i.e., from trauma-exposed parents with PTSD to their offspring), we will examine stable individual differences in gene activity that are subject to 'programming' by experience via epigenetic mechanisms (e.g., DNA methylation). These studies will focus on specific promoter regions of the glucocorticoid receptor (GR) in lymphocytes, a tissue we have demonstrated to be more responsive to glucocorticoids in PTSD. It will therefore be possible to associate epigenetic alterations in DNA methylation at GR promoter sites with genetic and non-genetic risk factors, and their interaction with trauma severity, towards the aim of understanding the simple, but as yet unanswered question of the role of trauma in the development of PTSD, and possibly the even more complex one of why some persons develop PTSD following trauma exposure while others do not. The coincidence of this unique and representative cohort, together with the expertise reflected in this multi-institutional team, will provide unambiguous information concerning the molecular-genetic basis of PTSD, PTSD vulnerability and even stress resistance. Hypothesis: We hypothesize that PTSD represents a specific phenotype, expressed in the presence of an environmental stressor that is characterized by an inadequate cortisol response at the time of a traumatic event leading (acutely) to an impaired reinstatement of physiologic homeostasis. We have suggested that, at its core, PTSD represents a failure to recover from the normal effects of trauma that can only be explained by models that consider the role of individual differences as modulators of the response to stress. Delineating the contributions of such differences to the development of PTSD, however, requires a broader assessment of vulnerability than has yet been accomplished, ideally including genotypic and molecular measures, in addition to clinical and functional (e.g., neuroendocrine) ones. It is only by examining polymorphisms in genes that are involved in stress-related hormone signaling, and their expression, that we can account for the full range of individual differences in the response to trauma.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 该提案旨在检查基因环境相互作用，这些相互作用有助于从纽约大都会地区的2750名男性和女性中选出的200人中的PTSD发展，暴露于世界贸易中心攻击。该队列在9月11日之后的六个月被招募，以确定这一事件导致的心理健康后果，并且足够大，足以对这种疾病的危险因素进行全面的调查。 我们将研究先前假设或证明与PTSD风险有关的临床和神经内分泌测量，与皮质醇信号的改变有关。 由于遗传因素有助于该生物系统的功能，因此我们将检查与糖皮质激素活性相关的几种基因的多态性，以及与PTSD病理生理学有关的肽基因和单胺能神经传递。 为了确定其他相关基因，我们将使用微阵列技术和定量聚合酶链反应检查表达谱。 验证的基因子集也将是与PTSD关联的基因分型。 此外，基于我们最近证明与PTSD和PTSD相关的皮质醇改变的非遗传层间传播的证据（即，从具有创伤性的父母有PTSD的父母到其后代），我们将检查基因活性稳定的个体差异，这些差异是通过经验来通过经验来通过经验来通过经验来通过经验来通过表皮机制（E.G.G.，e.g.g.，dna甲基化，dna甲基化）。 这些研究将集中在淋巴细胞中糖皮质激素受体（GR）的特定启动子区域，这是我们证明对PTSD中糖皮质激素的反应性的组织。 It will therefore be possible to associate epigenetic alterations in DNA methylation at GR promoter sites with genetic and non-genetic risk factors, and their interaction with trauma severity, towards the aim of understanding the simple, but as yet unanswered question of the role of trauma in the development of PTSD, and possibly the even more complex one of why some persons develop PTSD following trauma exposure while others do not. 这个独特而代表性的队列的巧合，以及在这个多机构团队中所反映的专业知识，将提供有关PTSD，PTSD脆弱性甚至压力抗性的分子遗传基础的明确信息。 假设：我们假设PTSD代表一种特定的表型，在存在环境压力源的情况下表达，其特征是在创伤事件（急性）导致生理稳态的重新定位的创伤事件时，皮质醇反应不足。 我们已经提出，从本质上讲，PTSD代表了未能从创伤的正常作用中恢复过来，只能通过将个体差异作为对压力响应的调节剂的作用的模型来解释。 但是，除了临床和功能（例如，神经内分泌）外，描述了这种差异对PTSD发展的贡献，需要对脆弱性进行更广泛的评估，包括基因型和分子测量。 只有通过检查与压力相关的激素信号传导及其表达涉及的基因中的多态性，我们才能解释对创伤反应的全部个体差异。