[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必要的，以推进治疗过程，并为患有这些毁灭性疾病的人类提供缓解。5-羟色胺(5-羟色胺)系统的紊乱与焦虑和抑郁有关，在S等位基因携带者的5-羟色胺转运体启动子区(5-HTTLPR)的长度多态性中发现了这些精神疾病与5-羟色胺相关的遗传易感性，S携带者显示5-HTT基因转录降低。恒河猴也携带这种遗传变异，为研究x基因与环境的相互作用提供了宝贵的资源。这项建议的总体目标是利用一种新的5-HT1A放射配基和PET成像方法在恒河猴身上检测5-HTTLPR多态、产前应激和5-HT1A结合指数之间的潜在关系。将对28只具有良好特征和严格控制的恒河猴进行PET扫描，这些恒河猴最初是由NIMH资助的一个群体，用于研究产前应激。[F-18]Mefway将用于在单次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-HT1ABmax的最大降幅将出现在具有S等位基因多态的产前应激组中，这表明基因x环境交互作用将是变异的主要成分。本项目中概述的工作将为扩展这项5-HT1APET成像研究提供框架，以调查环境变量，这些变量可能在更大的非人类灵长类动物队列中的精神病理易感性和基因表达中发挥重要作用，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会使一些人比其他人更容易患上与焦虑有关的或情绪障碍。5-羟色胺系统的紊乱与焦虑和抑郁有关，已发现一种相关的基因变异，可能使个人容易患上这些疾病。在这项建议中，我们的目标是在非人灵长类动物模型中使用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，检查编码5-羟色胺转运体基因短变异的携带者是否比那些基因变异长的携带者更受产前应激的影响。这项工作具有巨大的潜力，可以促进我们对环境经验如何与与焦虑相关的疾病的发展中的基因相互作用的了解。

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.