[F-18]Mefway PET to measure 5-HT1A receptors in gene x environment interactions

描述（由申请人提供）：进一步了解与焦虑和情绪障碍相关的多种遗传和环境风险因素是非常需要的，以推进治疗过程，并为遭受这些毁灭性疾病的人类提供救济。5-羟色胺（5-HT）系统的破坏与焦虑和抑郁有关，这些精神疾病的5-HT相关遗传易感性已在短等位基因携带者的5-HT转运子启动子区域（5-HTTLPR）的长度多态性中被确定，s携带者显示基因5-HTT转录减少。恒河猴也携带这种基因变异，为研究基因与环境的相互作用提供了宝贵的资源。本研究的总体目标是利用一种新的5-HT1A放射配体和恒河猴的PET成像方法来研究5-HTTLPR多态性、产前应激和5-HT1A结合指数之间的潜在关系。PET扫描将在28只恒河猴身上进行，这些恒河猴来自一个最初由NIMH资助的群体，用于研究产前压力。[F-18]Mefway将在单次PET成像实验中测量5- HT1A自身受体和突触后受体密度（Bmax）和表观KD。我们假设5-HT1A Bmax的最大减少将出现在具有s等位基因多态性的产前应激组，这表明基因与环境的相互作用将是方差的主要组成部分。本项目概述的工作将为扩展5-HT1A PET成像研究提供框架，以研究环境变量，这些环境变量可能在非人类灵长类动物的更大队列中对精神病理易感性和基因型表达起重要作用，并最终转化为人类群体。公共卫生相关性：紧张的生活经历可能使一些人比其他人更容易受到焦虑相关或情绪障碍的影响。血清素系统的破坏与焦虑和抑郁有关，并且已经确定了相关的遗传变异可能使个体易患这些疾病。在本研究中，我们的目标是利用非人类灵长类动物模型中5 -羟色胺系统的PET成像来研究产前应激对5 -羟色胺5HT1A受体的影响。特别是，为了检查编码5 -羟色胺转运体的基因短变异的携带者是否比那些基因长变异的携带者更深刻地受到产前压力的影响。这项工作具有很大的潜力，可以促进我们了解环境经验如何与基因相互作用，从而导致焦虑相关疾病的发展。

DESCRIPTION (provided by applicant): A further understanding of the multiple genetic and environmental risk factors associated with anxiety and mood disorders is greatly needed to advance courses of treatment and provide relief for humans suffering from these devastating illnesses. Disruption of the serotonin (5-HT) system has been implicated in anxiety and depression and a 5-HT related genetic predisposition for these psychiatric illnesses has been identified in the length polymorphism of the 5-HT transporter promoter region (5-HTTLPR) for carriers of the short (s) allele, with s carriers displaying reduced gene 5-HTT transcription. Rhesus monkeys, also carry this genetic variant and provide an invaluable resource for studying gene x environment interactions. The overall goal of this proposal is to utilize a novel 5-HT1A radioligand and PET imaging methods in the rhesus monkey to examine the potential relationship between 5-HTTLPR polymorphisms, prenatal stress and 5-HT1A binding indices. PET scans will be acquired on a well characterized and tightly controlled cohort of 28 rhesus monkeys, from a colony originally supported by NIMH funding to study prenatal stress. [F-18]Mefway will be used to measure 5- HT1A autoreceptor and postsynaptic receptor density (Bmax) and apparent KD in single PET imaging experiments. We hypothesize that the largest reduction in 5-HT1A Bmax will be seen in the prenatally stressed group with the s allele polymorphism, suggesting the gene x environment interaction will be the dominant component of the variance. The work outlined in this project will provide the framework for extending this research of 5-HT1A PET imaging to investigate environmental variables that may play a vital role in psychopathology predisposition and genotype expression in larger cohorts of nonhuman primates and for eventual translation into human populations. PUBLIC HEALTH RELEVANCE: Stressful life experiences may render some individuals more vulnerable than others to anxiety-related or mood disorders. Disruption of the serotonin system has been implicated in anxiety and depression and a related genetic variation has been identified that may predispose individuals for these illnesses. In this proposal, our goal is to use PET imaging of the serotonin system in the nonhuman primate model to study the effects of prenatal stress on the serotonin 5HT1A receptor. Particularly, to examine if carriers with a short variation of the gene for encoding the serotonin transporter are more profoundly affected by prenatal stress than those with long gene variation. This work holds great potential for advancing our knowledge of how environmental experiences interact with genes in the development of anxiety-related illnesses.