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翻译研究方法来检查恐惧生理学，分子遗传学和创伤后应激症状（PTSS）使用基因环境相互作用方法之间的关联。对恐惧的抑制已被概念化为创伤后应激障碍（PTSD）的中间神经生物学表型，通常被视为一种恐惧症。 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局限性的阻碍（这认识到创伤暴露在一定程度上是由可遗传因素确定的）。拟议的研究利用了一群独特的女性队列，该女性在2008年2月14日在伊利诺伊州北部大学进行大规模射击时参加了一项纵向研究。这种创伤暴露的命运性质最小化了基因 - 环境相关性的问题。拟议的研究基于大规模拍摄之前可用的广泛创伤和心理健康史，并预测恐惧生理学和垂体腺苷酸环化酶激活多肽（PACAP）将介导命运，共同的创伤和PTSS之间的关系。最近的研究（Ressler等，2011）报道了PACAP与女性但男性没有PTSD症状之间的联系。例如，女性证明了PACAP38血液水平之间的关联，并显着增加了与危险提示（CS+）和安全提示（CS-）之间的惊吓反射，而ADCYAP1R1受体SNP SNP RS2267735与PTSD和女性的恐惧条件显着相关，但没有男性。利用暴露于大规模射击的这种独特队列的子集（拟议的n = 150），据推测，当前的恐惧生理学（例如，实验室恐惧增强了恐惧的起点，恐惧的提示，恐惧歧视和恐惧灭绝和恐惧灭绝，以及与遗传和外围血液级别的差异相结合的偶然性（以及偶然的急速），将与外围级别的差异（E. e.G.射击前（大约在时间2的射击后大约27天），尤其是在大规模射击之前报告更广泛创伤史的女性中。 SNP RS2267735在雌激素反应元件中的位置在PTSD中性别差异的解释能力方面有希望。为了检查雌激素对PACAP-PAC1基因表达的影响，假设ADCYAP1R1甲基化水平将与较高（较低，雌激素的外周血水平较低）的个体中的PTS最密切相关。可以预料的是，WIL将告知对分子遗传学与PTSD风险之间联系的理解，尤其是在PTSD的性别差异方面，最终导致了PTSD治疗方法的更好量身定制。 公共卫生相关性：拟议的研究旨在提高对创伤后应激障碍（PTSD）根本原因的理解，这是公认的公共健康问题，具有重大的社会和个人成本。拟议的研究将解释夸张对惊人刺激的生理反应性的作用，结合周围 垂体腺苷酸环化酶的血液水平标记 - 激活多肽和雌激素，遗传因素和过去的创伤病史，在预测校园射击后创伤后压力方面发挥了作用。这项研究将扩大对PTSD原因的理解，并特别了解妇女对PTSD的更大风险的性质。