Biology of Risk of PTSD in Holocaust Survivor Offspring

描述（由申请人提供）：本申请是基于初步， 但令人信服的数据，暗示父母的创伤后应激障碍是一个假定的风险因素， 大屠杀幸存者后代的PTSD数据，在此充分描述 应用，引导我们研究PTSD风险的生物学相关性。到 确定是否以及在何种程度上观察到PTSD的生物学改变 与父母PTSD的危险因素有关，我们将比较临床数据 和具有父母创伤后应激障碍风险因素的个体的生物学数据， 没有这种风险因素的人。我们还试图区分生物 与PTSD风险相关的变量以及与 这种疾病的病理生理学。这将通过比较 具有PTSD风险因素的个体（但未发展为PTSD）， 那些患上创伤后应激障碍的人此外，我们建议研究 父母遭受创伤，但从未患上创伤后应激障碍的人， 父母没有受到严重创伤的人（即，大屠杀）。 这将允许确定是否父母暴露，与 父母的PTSD也可能是与生物后遗症相关的风险因素。 最后，我们希望研究生物学改变是否因人而异 有和没有抑郁症，主要涉及相同的 神经内分泌系统如创伤后应激障碍，在任何特定的条件下， 或者没有父母的创伤后应激障碍，自己的创伤后应激障碍，或者父母暴露于创伤。 两个神经内分泌刺激试验，在我们的实验室开发，将 在每个研究对象中进行。小剂量地塞米松抑制试验 (DST)将被用来评估负反馈抑制的 下丘脑-垂体-肾上腺（HPA）轴。甲吡酮兴奋试验 (MST)将被用于评估突触上激活（例如，CRF发布）通过 检查ACTH和11-脱氧皮质醇对甲吡酮的反应 局在每项测试中，我们将描述淋巴细胞糖皮质激素 受体（GR）数量在基础条件下，并响应地塞米松 (DEX)和甲吡酮给药，分别作为获得 GR敏感性（或反应性）指标。我们还将进行时间生物学 研究皮质醇、促肾上腺皮质激素 （ACTH）和去甲肾上腺素（NE）。为了实现这些目标，我们将研究数据 来自240名受试者，超过5年：80名后代的风险因素为 父母的PTSD，80个没有父母PTSD的后代，和80个人口统计学上的 1935年以后，父母不在欧洲的受试者。受试者 将被进一步细分，使有40在每个组与不 PTSD：每个亚组中有一半人目前患有抑郁症。因此我们 将在12个亚组中各招募20名受试者。

DESCRIPTION (provided by applicant): This application is based on preliminary, but compelling data, implicating parental PTSD as a putative risk factor for PTSD among offspring of Holocaust survivors. The data, fully described in this application, lead us to examine biologic correlates of risk for PTSD. To determine whether and to what extent biological alterations observed in PTSD are related to the risk factor of parental PTSD, we will compare clinical data and biological data in individuals with the risk factor of parental PTSD to those without this risk factor. We also seek to differentiate between biologic variables associated with risk for PTSD and those associated with the pathophysiology of this disorder. This will be accomplished by comparing individuals with the risk factor for PTSD (but have not developed PTSD) with those that have developed PTSD. Further, we propose to study whether individuals with trauma-exposed parents who never developed PTSD are similar to persons whose parents were not exposed to extreme trauma (i.e., the Holocaust). This will allow a determination of whether parental exposure, separate from parental PTSD, might also be a risk factor associated with biologic sequelae. Finally, we wish to study whether biologic alterations are different in persons with and without depressive disorders that principally involve the same neuroendocrine systems as PTSD, under any of the specific conditions of having or not having parental PTSD, one's own PTSD, or parental exposure to trauma. Two neuroendocrine stimulation tests, developed in our laboratory, will be performed in each study subject. The low-dose dexamethasone suppression test (DST) will be used to evaluate negative feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) axis. The metyrapone stimulation test (MST) will be used to assess suprapituitary activation (e.g., CRF release) via examination of the ACTH and 11-deoxycortisol response to metyrapone administration. In each test, we will characterize lymphocytic glucocorticoid receptor (GR) number under basal conditions, and in response to dexamethasone (DEX) and metyrapone administration, respectively, as a way of obtaining indices of GR sensitivity (or reactivity). We will also perform chronobiologic studies to characterize the circadian rhythm of cortisol, adrenocorticotropin (ACTH) and norepinephrine (NE). To accomplish these aims, we will examine data from 240 subjects over five years: 80 offspring with the risk factor of parental PTSD, 80 offspring without parental PTSD, and 80 demographically comparable subjects (whose parents were not in Europe after 1935). The subjects will be further subdivided so that there are 40 in each group with and without PTSD; half of each subgroup will have a current depressive disorder. Thus, we will recruit a total of 20 subjects in each of 12 subgroups.