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OIF/OEF退伍军人中一个严重且日益严重的问题。了解创伤后应激障碍风险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，(2)使创伤后应激障碍的个体化治疗方法成为可能。儿茶酚-O-甲基转移酶(COMT)基因编码区的多态COMTval158met最近在三个独立的研究中被认为与PTSD的风险有关。蛋氨酸(Met)等位基因纯合携带者在创伤后应激障碍(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的反应风险。健康的Met/Met携带者在恐惧消退方面表现出异常，而患有恐慌症的Met/Met携带者对暴露治疗的反应降低。因此，恐惧消退过程的中断可能解释了为什么Met携带者患创伤后应激障碍的风险增加。COMTval158 Met改变创伤后应激障碍风险并影响恐惧学习过程的机制尚不清楚。COMTval158met多态是一种编码突变，在这种突变中，Met等位基因纯合的受试者会降低酶活性，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是必要的。这个项目将使用一种新的“人源化”小鼠模型，在这种模型中，带有valine或蛋氨酸编码序列的人COMT基因被“敲入”到小鼠的COMT基因座上。该突变模型允许直接比较人类COMT、Val和MET等位基因对神经功能和行为的影响。这一独特的模型将用于确定(1)甲硫氨酸/甲硫氨酸异常在线索恐惧学习和消退中的DA受体机制和神经回路，以及(2)COMTval158met在其他创伤后应激障碍样症状和治疗反应中的作用。为了加强对临床的翻译，我们还将测试COMTval158met多态是否调节患有创伤后应激障碍的退伍军人对基于灭绝的治疗的反应。总体假设是，Met基因多态性增加了创伤后应激障碍的风险，并改变了暴露治疗的治疗反应，原因是皮质和杏仁核区域的儿茶酚胺信号发生了变化。在目标1中，我们使用人类COMTval158met多态的新敲门小鼠和药理学工具来检验这一假说，即改变皮质和杏仁核中DA受体D1、D2和D4信号是Met/Met小鼠消退缺陷和增加恐惧保持的基础。在目标2中，我们将使用COMTval158Met小鼠PTSD的捕食者应激模型来确定Met等位基因是否增加了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是否能阻止COMTval158Met小鼠因捕食者应激而引起的焦虑反应。在目标3中，我们将确定COMTval158met基因是否可以预测退伍军人创伤后应激障碍患者在接受基于消退或非消退的心理治疗时的治疗反应。该项目的发现将(1)促进我们对COMT和皮质DA系统在PTSD的病因和治疗中的理解(2)支持靶向治疗的开发，使Met携带者额叶皮质中的儿茶酚胺信号正常化(3)确定哌甲酯作为一种治疗PTSD的新疗法的潜在用途，以及(4)确定COMTval158met基因是否可以预测患有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.