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

基本信息

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
项目类别：
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

项目摘要

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，利用基因-环境相互作用的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与环境相关性的限制（承认创伤暴露部分由遗传因素决定）。这项拟议的研究利用了一组独特的女性，她们在 2008 年 2 月 14 日北伊利诺伊大学发生大规模枪击事件时参与了一项纵向研究。这种创伤暴露的致命性质最大限度地减少了基因与环境相关性的问题。拟议的研究建立在大规模枪击事件发生之前可获得的广泛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）将调解致命的共同创伤与创伤后应激障碍（PTSS）之间的关系。最近的研究（Ressler 等，2011）报告了女性 PACAP 与 PTSD 症状之间的联系，但男性则没有。例如，女性的 PACAP38 血液水平与危险提示 (CS+) 和安全提示 (CS-) 的惊吓反射显着增加之间存在关联，而 ADCYAP1R1 受体 SNP rs2267735 则与女性的 PTSD 和恐惧条件反射显着相关。但不是男性。利用这个暴露于大规模枪击事件的独特群体的子集（建议 N = 150），假设当前的恐惧生理学（例如，实验室恐惧增强了恐惧条件暗示、恐惧歧视和恐惧消退，以及黑暗增强）惊吓），结合遗传和外周血水平标记物（例如 PACAP），将预测从射击前到射击后评估的 PTSS 差异风险（大约时间 2) 枪击后 27 天，尤其是在大规模枪击事件前报告有更广泛创伤史的女性。 SNP rs2267735 在雌激素反应元件中的位置有望解释 PTSD 中的性别差异。为了检查雌激素对 PACAP-PAC1 基因表达的影响，假设外周血雌激素水平较高（而不是较低）的个体中 ADCYAP1R1 甲基化水平与 PTSS 的相关性最强。预计这些发现将有助于理解分子遗传学与 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 治疗方法。公共健康相关性：拟议的研究旨在增进对创伤后应激障碍（PTSD）根本原因的理解，这是一个公认的公共健康问题，会造成巨大的社会和个人成本。拟议的研究将结合外周神经系统来解释夸大对令人震惊的刺激的生理反应的作用垂体腺苷酸环化酶激活多肽和雌激素的血液水平标记物、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方面发挥着作用。这项研究将加深对创伤后应激障碍成因的理解，特别是揭示女性患创伤后应激障碍的风险更大的本质。