GENETICS, ENDOCRINOLOGY AND PTSD RISK IN POPULATION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 这项建议试图从纽约大都会地区暴露于世界贸易中心袭击中的2750名男性和女性中挑选出200人，研究导致创伤后应激障碍发生的基因-环境相互作用。这个队列是在9·11事件后六个月招募的，为了确定这一事件造成的精神健康后果，已经进行了纵向跟踪，并且足够大，足以对这种疾病的风险因素进行全面调查。我们将检查临床和神经内分泌指标，以前假设或证明与创伤后应激障碍风险相关，与皮质醇信号的改变有关。由于遗传因素参与了这一生物系统的功能，我们将研究与糖皮质激素活性相关的几个基因的多态性，以及与创伤后应激障碍病理生理学有关的肽能和单胺能神经传递。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式反应来检测表达谱。被验证的基因子集也将进行与创伤后应激障碍相关的基因分型。此外，基于我们最近关于创伤后应激障碍和与创伤后应激障碍相关的皮质醇改变的代际非遗传性传播的证据(即，从创伤暴露的患有创伤后应激障碍的父母传给他们的后代)，我们将通过表观遗传机制(例如DNA甲基化)来检验稳定的个体基因活性差异，这些差异受到经验的“编程”。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，我们已经证明，在创伤后应激障碍患者中，这一组织对糖皮质激素更敏感。因此，有可能将GR启动子区DNA甲基化的表观遗传学改变与遗传和非遗传风险因素及其与创伤严重程度的相互作用联系起来，以期了解创伤在创伤后的发展中的作用这一简单但尚未回答的问题，以及可能更复杂的为什么有些人在创伤暴露后患上创伤后应激障碍，而另一些人不会。这一独特和具有代表性的队列的巧合，加上这个多机构团队所反映的专业知识，将提供关于创伤后应激障碍的分子遗传学基础、创伤后应激障碍脆弱性甚至应激抵抗的明确信息。 假设：我们假设创伤后应激障碍代表一种特定的表型，表现在环境应激源的存在，其特征是创伤性事件时皮质醇反应不足，导致(急性)生理稳态的受损恢复。我们认为，从本质上讲，创伤后应激障碍代表着无法从创伤的正常影响中恢复过来，只有考虑到个体差异作为压力反应调节器的模型才能解释这一点。然而，要描述这种差异对创伤后应激障碍发展的贡献，需要对脆弱性进行比迄今已完成的更广泛的评估，理想情况下，除了临床和功能(如神经内分泌)措施外，还应包括基因和分子措施。只有通过检测与压力相关的激素信号的基因及其表达的多态，我们才能解释创伤反应的各种个体差异。

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.