Role of COMTval158met in PTSD risk and treatment response

描述（由申请人提供）： 与战斗有关的创伤后应激障碍仍然是法语国家组织/持久自由行动退伍军人中一个严重和日益严重的问题。了解PTSD风险和调节治疗反应的生物学机制将有助于（1）识别新的治疗策略和（2）实现PTSD的个体化治疗方法。儿茶酚-O-甲基转移酶（COMT）基因编码区的多态性COMTval 158 met最近在3项独立的研究中与PTSD的风险有关。甲硫氨酸（Met）等位基因纯合子携带者在PTSD患者人群中更为普遍，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携带者表现出恐惧消退的异常，而患有惊恐障碍的Met/Met携带者表现出对暴露治疗的反应降低。因此，恐惧消退过程的中断可以解释为什么Met携带者表现出PTSD风险增加。COMTval 158 met改变PTSD风险和影响恐惧学习过程的机制尚不清楚。COMTval 158 met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的儿茶酚胺降解。最近的研究表明，额叶皮层中的多巴胺（DA）信号对于恐惧消退学习以及对长期压力影响的弹性是必要的。该项目将使用一种新的“人源化”小鼠模型，其中具有缬氨酸或甲硫氨酸编码序列的人COMT基因被“敲入”小鼠Comt基因位点。该突变体模型允许直接比较人COMT瓦尔和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）线索恐惧学习和消退中Met/Met异常的DA受体机制和神经回路，以及（2）COMTval 158 met在其他PTSD样症状和治疗反应中的作用。为了提高临床的转化率，我们还将测试COMTval 158 met多态性是否能调节创伤后应激障碍退伍军人对预防性治疗的反应。总的假设是，Met多态性赋予PTSD的风险，并改变暴露疗法的治疗反应，由于皮质和杏仁核区域中的儿茶酚胺信号的改变。在目标1中，我们使用新的敲入小鼠的人类COMTval 158 met多态性和药理学工具来测试这一假设，即改变DA受体D1，D2和D4信号在皮质和杏仁核的基础上灭绝缺陷和增加的恐惧保留在Met/Met小鼠。在目标2中，我们将在COMTval 158 met小鼠中使用PTSD的捕食者应激模型来确定Met等位基因是否增加对创伤对焦虑样行为的持久影响的反应性。我们还将确定优先增强皮质DA信号传导并在临床上可用的哌甲酯是否阻断COMTval 158 met小鼠中由捕食者应激诱导的焦虑反应。在目标3中，我们将确定COMTval 158 met基因型是否能预测接受预防性或非灭绝性心理治疗的PTSD退伍军人的治疗反应。该项目的发现将（1）促进我们对COMT和皮质DA系统在PTSD病因学和治疗中的理解（2）支持开发靶向治疗，使Met携带者额叶皮质中的儿茶酚胺信号正常化（3）确定哌甲酯作为PTSD新治疗的潜在效用（4）确定COMTval 158 met基因型是否能预测退伍军人PTSD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.