项目来源

美国卫生和人类服务部基金(HHS)

项目主持人

TUMA, FARRIS K.

项目受资助机构

MCLEAN HOSPITAL

立项年度

2016

立项时间

未公开

项目编号

5R01MH096764-06

研究期限

未知 / 未知

项目级别

国家级

受资助金额

402077.00美元

学科

Anxiety Disorders; Brain Disorders; Clinical Research; Estrogen; Genetics; Mental Health; Mental Illness; Post-Traumatic Stress Disorder (PTSD);

学科代码

未公开

基金类别

Non-SBIR/STTR RPGs

关键词

未公开

参与者

RESSLER, KERRY J.

参与机构

NATIONAL INSTITUTE OF MENTAL HEALTH

项目标书摘要：DESCRIPTION (provided by applicant): Post-traumatic stress disorder (PTSD) is a maladaptive and debilitating psychiatric disorder characterized by an extreme sense of fear at the time of trauma occurrence, with characteristic re- experiencing, avoidance, and hyperarousal symptoms in the months and years following the trauma. PTSD has a prevalence of approximately 6%, but can occur in up to 25% of subjects who have experienced severe psychological trauma, such as combat veterans, refugees, and assault victims. The differential risk determining those who do vs. those who do not develop PTSD is multi-determined: 1) it is in part genetic, with approximately a 30-40% risk heritability for PTSD following trauma; 2) it in par depends on sex, with women having approximately twice the risk as men to develop PTSD following trauma; and 3) it in part depends on past personal history, including adult and childhood trauma and psychological factors which may differentially mediate fear and emotion regulation. Pituitary adenylate cyclase-activating polypeptide (PACAP) has previously been identified as a critical regulator of the stress response across species. We have recently shown that PACAP and its PAC1 receptor (PAC1R) may be critical mediators of abnormal processes following psychological trauma, such as with posttraumatic stress disorder (PTSD) in humans. We recently found, in heavily traumatized human subjects, a sex-specific association of PACAP blood levels with fear physiology, PTSD diagnosis and symptoms in females (N=64, replication N=74, p<0.005). Using a tag-SNP genetic approach (44 single nucleotide polymorphisms, SNPs) spanning the PACAP (ADCYAP1) and PAC1R (ADCYAP1R1) genes, we found a sex-specific association between a single SNP (rs2267735) and fear and PTSD symptoms. The SNP residing in a putative estrogen response element (ERE) within PAC1R, predicts fear response, PTSD diagnosis and symptoms in females (combined initial and replication samples: N=1237; p<2x10-5). The presence of this SNP is inversely correlated with PAC1R mRNA expression, and methylation of PAC1R is associated with PTSD (p < 0.001). Complementing these human data, we found that PAC1R mRNA is induced with fear conditioning or estrogen replacement in rodent models. These data suggest that perturbations in the PACAP/PAC1R pathway are involved in abnormal fear responses underlying PTSD. This proposal aims to extend these initial findings with a larger sample size, identifying peripheral markers of PACAP/PAC1 pathway activity as a biomarker for PTSD. We will further extend these data by examining the role of estrogen, PAC1R DNA methylation / histone acetylation, and PAC1R mRNA expression on PTSD symptoms and fear physiology in traumatized female subjects. We will further examine the mechanisms of PAC1 regulation using human lymphoblast cell lines of differing PAC1 rs2267735 genotypes.