GENETICS, ENDOCRINOLOGY AND PTSD RISK IN POPULATION

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 这项建议旨在研究基因-环境的相互作用，有助于创伤后应激障碍的发展，在200人中选择了一个良好的表征样本的2750名男性和女性在纽约大都市区，暴露于世界贸易中心的攻击。该队列是在9月11日之后6个月招募的，为了确定该事件导致的心理健康后果，对其进行了纵向跟踪，并且足够大，足以对该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措施，以前假设或证明与创伤后应激障碍的风险，皮质醇信号的改变有关。 由于遗传因素有助于这个生物系统的功能，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PTSD病理生理学中涉及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测表达谱。 被验证的基因子集也将被基因分型为与PTSD相关。 此外，根据我们最近关于创伤后应激障碍的非遗传代际传递和与创伤后应激障碍相关的皮质醇改变的证据（即，从患有创伤后应激障碍的创伤暴露父母到他们的后代），我们将检查基因活性的稳定个体差异，这些差异通过表观遗传机制（例如，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）的特异性启动子区域，我们已经证明淋巴细胞对PTSD中的糖皮质激素反应更敏感。 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，以了解创伤在PTSD发展中的作用这一简单但尚未回答的问题，以及为什么有些人在创伤暴露后发展为PTSD而其他人没有发展为PTSD这一更复杂的问题。 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，将提供有关PTSD，PTSD脆弱性甚至抗应激能力的分子遗传基础的明确信息。 假设：我们假设创伤后应激障碍代表了一种特定的表型，在环境应激源的存在下表达，其特征是在创伤事件发生时皮质醇反应不足，导致（急性）生理稳态的恢复受损。 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，这只能通过考虑个体差异作为压力反应调节器的模型来解释。 然而，描述这些差异对PTSD发展的贡献，需要比尚未完成的更广泛的脆弱性评估，理想情况下，除了临床和功能（例如，神经内分泌）的。 只有通过检测与应激相关的激素信号及其表达有关的基因多态性，我们才能解释创伤反应中的所有个体差异。

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.