Role of COMTval158met in PTSD risk and treatment response

COMTval158met 在 PTSD 风险和治疗反应中的作用

• 批准号: 8967100
• 负责人: Victoria B Risbrough
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-10-01 至 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8967100
• 关键词: Affect; Alleles; Amygdaloid structure; Animal Model; Anxiety; Behavior; Behavioral; Biological; Caring; Catecholamines; Catechols; Clinic; Code; Complement; Consent; Cues; Development; Dopamine; Dopamine D1 Receptor; Dopamine Receptor; Dose; Elements; Etiology; Exhibits; Exposure to; Extinction (Psychology); Fright; Funding; Future; Gene Mutation; Genes; Genetic Polymorphism; Genotype; Human; Knock-in; Knock-in Mouse; Learning; Link; Long-Term Effects; Methionine; Methylphenidate; Methyltransferase; Methyltransferase Gene; Mission; Modeling; Mus; Mutation; Neurophysiology - biologic function; Panic Disorder; Participant; Patients; Phenotype; Population; Positioning Attribute; Post-Traumatic Stress Disorders; Process; Psychotherapy; Recovery; Research Personnel; Risk; Role; Safety; Short-Term Memory; Signal Transduction; Stress; Symptoms; Techniques; Testing; Translating; Translations; Trauma; Valine; Veterans; Withdrawal; Work; anxiety-like behavior; base; clinically relevant; combat; conditioned fear; dopamine system; frontal lobe; humanized mouse; individualized medicine; learning extinction; meetings; mouse model; mutant; neural circuit; novel; patient population; predicting response; predictive of treatment response; public health relevance; response; risk variant; social; tool; treatment response; treatment strategy

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.

描述（由申请人提供）： 与战斗有关的PTSD在OIF/OEF退伍军人人口中仍然是一个重大且日益严重的问题。了解PTSD和调节治疗反应风险的生物学机制将有助于（1）鉴定新型治疗策略，以及（2）启用PTSD的个性化治疗方法。最近在3项单独的研究中，Catechol-O-甲基转移酶（COMT）基因COMTVAL158MET的编码区域的多态性与PTSD的风险有关。蛋氨酸（Met）等位基因的纯合子在PTSD患者人群中更为普遍，而MET等位基因增加了应对中度创伤暴露的风险。健康的MET/MET携带者在恐惧灭绝中表现出异常，并且有恐慌症的MET/MET载体表现出对暴露疗法的反应减少。因此，恐惧灭绝过程中的中断可能解释了为什么大都会携带者表现出更大的PTSD风险。 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，因此额叶皮质中的儿茶酚胺降解减少。最近的研究表明，额叶皮层中的多巴胺（DA）信号传导对于恐惧灭绝学习以及对压力的长期影响的弹性是必要的。该项目将使用一种新型的“人性化”小鼠模型，其中人类COMT基因具有valine或Methione编码序列被“敲入”小鼠COMT基因基因座。该突变模型允许直接比较人类COMT VAL并符合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）在提示恐惧学习和灭绝的MET/MET异常的DA受体机制和神经回路以及（2）COMTVAL158MET在其他PTSD样症状以及对治疗的反应中的作用。为了增强对诊所的翻译，我们还将测试COMTVAL158MET多态性是否调节对PTSD退伍军人的基于灭绝的治疗的反应。总体假设是，由于皮质和杏仁核区域中儿茶酚胺信号的改变，MET多态性赋予了PTSD的风险，并改变了对暴露疗法的治疗反应。在AIM 1中，我们将新型的敲蛋白小鼠用于人类COMTVAL158MET多态性和药理学工具来检验假说，即在皮层中改变了DA受体D1，D2和D4信号传导，而杏仁核则是Met/Met/Met/Met/Met小鼠中灭绝缺陷的基础。在AIM 2中，我们将使用COMTVAL158MET小鼠中PTSD的捕食者应力模型来确定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。我们还将确定优先增强皮质DA信号并在临床上可用的甲基苯甲酸酯是否会阻止COMTVAL158MET小鼠中捕食者应激引起的焦虑反应。在AIM 3中，我们将确定COMTVAL158MET基因型是否可以预测基于灭绝或基于非灭绝的PTSD退伍军人的治疗反应。该项目的发现将（1）在病因和治疗PTSD（2）支持开发目标治疗的病因和治疗中对COMT和皮质DA系统的理解，以使MET携带者额叶皮质中的儿茶酚胺信号正常化（3）确定甲基化治疗方法的潜在效用（4）在PTSD和4）中的潜在效用（如果对PTSD和4）进行了预测。 PTSD。