Role of COMTval158met in PTSD risk and treatment response

描述（由申请人提供）： 与战斗相关的创伤后应激障碍 (PTSD) 仍然是 OIF/OEF 退伍军人中一个严重且日益严重的问题。了解 PTSD 风险背后的生物学机制并调节治疗反应将有助于 (1) 确定新的治疗策略，以及 (2) 实现 PTSD 的个体化治疗方法。最近的 3 项独立研究表明，儿茶酚邻位甲基转移酶 (COMT) 基因 COMTval158met 编码区的多态性与 PTSD 风险相关。蛋氨酸 (Met) 等位基因纯合子携带者在 PTSD 患者群体中更为普遍，Met 等位基因增加了对中度创伤暴露做出反应的风险。健康的 Met/Met 携带者在恐惧消退方面表现出异常，而患有惊恐障碍的 Met/Met 携带者则表现出对暴露疗法的反应减弱。因此，恐惧消退过程的中断可以解释为什么 Met 携带者患 PTSD 的风险增加。 COMTval158met 改变 PTSD 风险并影响恐惧学习过程的机制尚不清楚。 COMTval158met 多态性是一种编码突变，其中 Met 等位基因纯合的受试者酶活性降低，从而减少额叶皮质中儿茶酚胺的降解。最近的研究表明，额叶皮质中的多巴胺 (DA) 信号对于恐惧消退学习以及对压力的长期影响的恢复能力是必要的。该项目将使用一种新型“人源化”小鼠模型，其中具有缬氨酸或甲硫酮编码序列的人类 COMT 基因被“敲入”到小鼠 Comt 基因座中。该突变模型可以直接比较人类 COMT val 和 met 等位基因对神经功能和行为的影响。这种独特的模型将用于确定 (1) DA 受体机制和神经回路，这些受体机制和神经回路是 Met/Met 异常在提示性恐惧学习和消退中的作用，以及 (2) COMTval158met 在其他 PTSD 样症状和治疗反应中的作用。为了加强向临床的转化，我们还将测试 COMTval158met 多态性是否调节患有 PTSD 的退伍军人对基于灭绝的治疗的反应。总体假设是，Met 多态性会带来 PTSD 的风险，并由于皮质和杏仁核区域儿茶酚胺信号的改变而改变对暴露疗法的治疗反应。在目标 1 中，我们使用人类 COMTval158met 多态性的新型敲入小鼠和药理学工具来测试以下假设：皮质和杏仁核中 DA 受体 D1、D2 和 D4 信号传导的改变是 Met/Met 小鼠消退缺陷和恐惧保留增加的基础。在目标 2 中，我们将使用 COMTval158met 小鼠的 PTSD 捕食者应激模型来确定 Met 等位基因是否会增加对创伤对焦虑样行为的持久影响的反应性。我们还将确定哌醋甲酯（优先增强皮质 DA 信号传导且在临床上可用）是否可以阻断 COMTval158met 小鼠捕食者应激引起的焦虑反应。在目标 3 中，我们将确定 COMTval158met 基因型是否可以预测患有 PTSD 的退伍军人接受基于消退或非消退的心理治疗的治疗反应。该项目的研究结果将 (1) 增进我们对 COMT 和皮质 DA 系统在 PTSD 病因和治疗中的理解 (2) 支持开发使 Met 携带者额叶皮层儿茶酚胺信号转导正常化的靶向治疗方法 (3) 确定哌醋甲酯作为 PTSD 新型治疗方法的潜在效用，以及 (4) 确定 COMTval158met 基因型是否可以预测患有 PTSD 的退伍军人的治疗反应。

DESCRIPTION (provided by applicant): Combat-related PTSD remains a significant and growing problem in the OIF/OEF veteran population. Understanding biological mechanisms that underlie risk for PTSD and modulate treatment responses will aid in (1) identification of novel treatment strategies and (2) enable individualized treatment approaches for PTSD. A polymorphism in the coding region of the catechol-o-methyltransferase (COMT) gene, COMTval158met, has recently been linked to risk for PTSD across 3 separate studies. Carriers homozygous for the methionine (Met) allele are more prevalent in PTSD patient populations, with the Met allele increasing risk of responding to moderate trauma exposure. Healthy Met/Met carriers exhibit abnormalities in fear extinction and Met/Met carriers with panic disorder exhibit reduced responses to exposure therapy. Hence, disruptions in fear extinction processes may explain why Met carriers exhibit increased risk for PTSD. The mechanisms by which COMTval158met alters risk for PTSD and affects fear learning processes are not understood. The COMTval158met polymorphism is a coding mutation in which subjects homozygous for the Met allele have reduced enzymatic activity with consequently reduced catecholamine degradation in frontal cortex. Recent studies suggest that dopamine (DA) signaling in the frontal cortex is necessary for fear extinction learning as well as for resiliency to long-term effects of stress. This project will use a novel "humanized" mouse model in which the human COMT gene with either the valine or methione coding sequence is "knocked-in" to the mouse Comt gene locus. This mutant model allows for direct comparison of the human COMT val and met allele effects on neural functions and behavior. This unique model will be used to determine (1) the DA receptor mechanism and neural circuits underlying Met/Met abnormalities in cued fear learning and extinction and (2) the role of COMTval158met in other PTSD-like symptoms and response to treatment. To enhance translation to the clinic, we will also test whether the COMTval158met polymorphism modulates the response to extinction-based treatments in veterans with PTSD. The overall hypothesis is that the Met polymorphism confers risk for PTSD and alters treatment response to exposure therapy due to alterations in catecholamine signaling in cortex and amygdala regions. In aim 1 we use novel knockin mice for the human COMTval158met polymorphism and pharmacological tools to test the hypothesis that altered DA receptor D1, D2 and D4 signaling in the cortex and amygdala underlies the extinction deficits and increased fear retention in Met/Met mice. In aim 2 we will use the predator stress model of PTSD in COMTval158met mice to determine if the Met allele increases responsivity to enduring effects of trauma on anxiety-like behaviors. We will also determine if methylphenidate, which preferentially enhances cortical DA signaling and is clinically available, blocks the anxiety responses induced by predator stress in COMTval158met mice. In aim 3, we will determine if the COMTval158met genotype predicts treatment response in Veterans with PTSD undergoing either extinction-based or non-extinction based psychotherapy. The findings from this project will (1) advance our understanding of COMT and cortical DA system in the etiology and treatment of PTSD (2) support development of targeted treatments that normalize catecholamine signaling in the frontal cortex of Met carriers (3) determine the potential utility of methylphenidate as a novel treatment for PTSD and (4) determine if the COMTval158met genotype is predictive of treatment responses in Veterans with PTSD.