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

描述（由申请人提供）：非常需要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，以推进治疗过程，并为患有这些毁灭性疾病的人提供救济。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（s）等位基因携带者的5-HT转运蛋白启动子区（5-HTTLPR）的长度多态性中得到鉴定，其中s携带者显示基因5-HTT转录降低。恒河猴也携带这种遗传变异，为研究基因与环境的相互作用提供了宝贵的资源。本提案的总体目标是利用一种新的5-HT 1A放射性配体和PET成像方法在恒河猴中检查5-HTTLPR多态性，产前应激和5-HT 1A结合指数之间的潜在关系。PET扫描将在28只恒河猴的良好表征和严格控制的队列中进行，这些恒河猴来自最初由NIMH资助研究产前应激的群体。[F-18]Mefway将用于在单次PET成像实验中测量5-HT 1A自身受体和突触后受体密度（Bmax）和表观KD。我们假设，5-HT 1A Bmax的最大降幅将出现在产前应激组与s等位基因多态性，这表明基因x环境的相互作用将是方差的主要组成部分。该项目中概述的工作将为扩展5-HT 1A PET成像的研究提供框架，以调查环境变量，这些变量可能在较大的非人灵长类动物队列中的精神病理学易感性和基因型表达中发挥重要作用，并最终转化为人类。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患上焦虑相关或情绪障碍。5-羟色胺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。在这个建议中，我们的目标是使用PET成像的5-羟色胺系统在非人灵长类动物模型，研究产前压力对5-羟色胺5 HT 1A受体的影响。特别是，要检查是否携带者的编码5-羟色胺转运蛋白的基因的短变异更深刻地影响产前压力比那些长的基因变异。这项工作具有很大的潜力，可以促进我们对环境经验如何与焦虑相关疾病的发展中的基因相互作用的认识。

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.