GENETICS, ENDOCRINOLOGY AND PTSD RISK IN POPULATION

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。本研究旨在研究基因与环境之间的相互作用对创伤后应激障碍的影响，研究对象是从纽约大都会区2750名受到世贸中心袭击的男性和女性中挑选出来的200人。该队列是在9 / 11事件发生6个月后招募的，为了确定该事件对心理健康造成的影响，对其进行了纵向跟踪，其规模足够大，可以对这种疾病的风险因素进行全面调查。我们将检查先前假设或证明与PTSD风险相关的临床和神经内分泌指标，这些指标与皮质醇信号的改变有关。由于遗传因素影响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PTSD病理生理相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反应检查表达谱。被验证的基因子集也将被基因分型以确定与创伤后应激障碍的关联。此外，基于我们最近关于创伤后应激障碍的非遗传代际传播和与创伤后应激障碍相关的皮质醇改变的证据（即，从创伤暴露的创伤后应激障碍父母到他们的后代），我们将研究基因活性的稳定个体差异，这些差异受表观遗传机制（例如，DNA甲基化）的经验“编程”影响。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，我们已经证明该组织对创伤后应激障碍患者的糖皮质激素反应更灵敏。因此，有可能将GR启动子位点DNA甲基化的表观遗传改变与遗传和非遗传风险因素，以及它们与创伤严重程度的相互作用联系起来，以理解创伤在PTSD发展中的作用这一简单但尚未得到解答的问题，以及可能更复杂的问题，即为什么有些人在创伤暴露后患上PTSD，而另一些人却没有。这一独特而具有代表性的队列的巧合，以及这个多机构团队所反映的专业知识，将为PTSD的分子遗传基础、PTSD易感性甚至抗逆性提供明确的信息。假设：我们假设PTSD代表了一种特定的表型，在环境压力源的存在下表达，其特征是在创伤性事件时皮质醇反应不足，导致（急性）生理稳态受损的恢复。我们认为，从本质上讲，创伤后应激障碍是一种无法从创伤的正常影响中恢复的症状，这种症状只能通过个体差异作为应激反应调节因子的模型来解释。然而，描述这些差异对创伤后应激障碍发展的贡献，需要比目前所完成的更广泛的易感性评估，理想情况下，除了临床和功能（如神经内分泌）测量外，还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及其表达有关的基因多态性，我们才能解释对创伤反应的全部个体差异。

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.