Biomarkers for Posttraumatic Stress in Women Following a Campus Mass Shooting

校园大规模枪击事件后女性创伤后应激障碍的生物标志物

• 批准号: 8434465
• 负责人: HOLLY K ORCUTT
• 金额: $ 40.28万
• 依托单位: NORTHERN ILLINOIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-10 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8434465
• 关键词: Biological Factors; Biological Markers; Bipolar Disorder; Blood; Cues; Data; Discrimination; Disease; Enrollment; Environment; Estrogens; Extinction (Psychology); Family Study; Female; Fright; Gene Expression; Genes; Genetic; Genetic Research; Genetic Risk; Heritability; Illinois; Image; Impulsivity; Individual; Intervention; Knowledge; Laboratories; Light; Link; Location; Longitudinal Studies; Mediating; Mental Depression; Mental Health; Methods; Methylation; Molecular Genetics; Nature; Neurobiology; PACAP38; Pathogenesis; Phenotype; Physiological; Physiology; Play; Post-Traumatic Stress Disorders; Public Health; Publishing; Recording of previous events; Recruitment Activity; Reflex action; Reporting; Research; Research Methodology; Response Elements; Risk; Risk Adjustment; Risk Factors; Risk-Taking; Role; Safety; Sampling; Schizophrenia; Sex Characteristics; Stimulus; Stress; Symptoms; System; Time; Translational Research; Trauma; Twin Studies; Universities; Woman; biological adaptation to stress; cohort; conditioned fear; cost; demographics; disorder risk; gene environment interaction; innovation; male; peripheral blood; pituitary adenylate cyclase activating polypeptide; psychopharmacologic; receptor; research study; revictimization

DESCRIPTION (provided by applicant): The specific aim of the proposed study is to utilize innovative translational research methods to examine the association between fear physiology, molecular genetics and posttraumatic stress symptoms (PTSS) using a gene-environment interaction approach. Inhibition of fear has been conceptualized as an intermediate neurobiological phenotype of posttraumatic stress disorder (PTSD), commonly viewed as a disorder of fear. PTSD is an ideal Candidate for a gene-environment interaction approach; however, existing molecular genetics research is hampered by the limitation of gene-environment correlation (which recognizes the fact that trauma exposure is in part determined by heritable factors). The proposed study utilizes a unique cohort of females enrolled in a longitudinal study at the time of a mass shooting at Northern Illinois University on February 14, 2008. The fateful nature of this trauma exposure minimizes the problem of gene-environment correlation. The proposed study builds upon the extensive trauma and mental health history available prior to the mass shooting and predicts that fear physiology and the pituitary adenylate cyclase-activating polypeptide (PACAP) will mediate the relationship between a fateful, shared trauma and PTSS. Recent research (Ressler et al., 2011) has reported a link between PACAP and PTSD symptoms in females but not males. For example, females demonstrated an association between PACAP38 blood levels and significantly increased startle reflexes to both the danger cue (CS+) and the safety cue (CS-), while the ADCYAP1R1 receptor SNP rs2267735 demonstrated significant association with PTSD and fear conditioning in females, but not males. Utilizing a subset (proposed N = 150) of this unique cohort exposed to a mass shooting, it is hypothesized that current fear physiology (e.g., laboratory fear potentiated startl to a fear conditioned cue, fear discrimination and fear extinction, as well as dark enhanced startle), combined with genetic and peripheral blood level markers (e.g., PACAP), will predict differential risk for PTSS as assessed from pre- to post-shooting (approximately 27 days post-shooting at Time 2), particularly among females who reported a more extensive trauma history prior to the mass shooting. The location of SNP rs2267735 within an estrogen response element holds promise in terms of explanatory power for sex differences in PTSD. To examine the impact of estrogen on PACAP-PAC1 gene expression, it is hypothesized that ADCYAP1R1 methylation levels will be most strongly related to PTSS among individuals with higher, as opposed to lower, levels of peripheral blood levels of estrogen. It is anticipated that findings wil inform understanding of the link between molecular genetics and the risk for PTSD, particularly with regard to sex differences in PTSD, ultimately leading to better tailoring of treatment methods for PTSD. PUBLIC HEALTH RELEVANCE: The proposed research aims to advance understanding of the underlying causes of posttraumatic stress disorder (PTSD), which is a recognized public health problem with significant societal and individual costs. The proposed research will explain the role that exaggerated physiological reactivity to startling stimuli, in combination with peripheral blood level markers of pituitary adenylate cyclase- activating polypeptide and estrogen, genetic factors, and past trauma history, plays in predicting posttraumatic stress following a campus shooting. This research will broaden understanding of the causes of PTSD and will shed light in particular on the nature of women's greater risk for PTSD.

描述（由申请人提供）：拟议研究的具体目的是利用创新的转化研究方法，使用基因-环境相互作用方法来检查恐惧生理学，分子遗传学和创伤后应激症状（PTSS）之间的关联。恐惧抑制被认为是创伤后应激障碍（PTSD）的一种中间神经生物学表型，通常被视为恐惧障碍。PTSD是基因-环境相互作用方法的理想候选者;然而，现有的分子遗传学研究受到基因-环境相关性的限制（承认创伤暴露部分由遗传因素决定的事实）。拟议的研究利用了一个独特的队列的女性参加了纵向研究时，大规模射击在北方伊利诺伊大学于2008年2月14日。这种创伤暴露的致命性质使基因-环境相关性问题最小化。这项拟议的研究建立在大规模枪击事件之前广泛的创伤和心理健康史的基础上，并预测恐惧生理学和垂体腺苷酸环化酶激活多肽（PACAP）将介导致命的，共同的创伤和PTSS之间的关系。最近的研究（Ressler等人，2011）报道了PACAP与女性而非男性的PTSD症状之间的联系。例如，女性表现出PACAP 38血液水平与危险提示（CS+）和安全提示（CS-）的惊吓反射显著增加之间的关联，而ADCYAP 1 R1受体SNP rs 2267735表现出与女性的PTSD和恐惧条件反射显著相关，但不是男性。利用暴露于大规模枪击事件的该独特队列的子集（提出的N = 150），假设当前的恐惧生理学（例如，实验室恐惧增强START 1到恐惧条件线索、恐惧辨别和恐惧消退，以及黑暗增强惊吓），与遗传和外周血水平标记物（例如，PACAP），将预测PTSS的差异风险，从射击前到射击后（时间2射击后约27天）进行评估，特别是在大规模射击前报告更广泛创伤史的女性中。SNP rs 2267735在雌激素反应元件中的位置在解释PTSD性别差异方面有希望。为了研究雌激素对PACAP-PAC 1基因表达的影响，假设ADCYAP 1 R1甲基化水平与外周血雌激素水平较高而不是较低的个体中PTSS的相关性最强。预计这些发现将有助于了解分子遗传学与PTSD风险之间的联系，特别是关于PTSD的性别差异，最终导致更好地定制PTSD的治疗方法。 公共卫生相关性：拟议的研究旨在促进对创伤后应激障碍（PTSD）的根本原因的理解，这是一个公认的公共卫生问题，具有重大的社会和个人成本。这项拟议中的研究将解释对惊人刺激的夸大生理反应的作用，以及周围神经系统的作用。 血液中垂体腺苷酸环化酶激活多肽和雌激素的水平，遗传因素和过去的创伤史，在预测校园枪击事件后的创伤后应激中发挥作用。这项研究将扩大对创伤后应激障碍原因的理解，并将特别阐明女性患创伤后应激障碍风险更大的本质。