Genetic analysis of Htr2c RNA editing in amygdala

描述(由申请人提供)：Htr2c RNA编辑通过产生多达24种具有不同信号转导特性的受体亚型来改变5-HT2C受体对大脑功能的潜在贡献。Htr2c RNA编辑是5-羟色胺能功能和精神疾病的重要内表型，了解这种变异的遗传病因是一个重要的目标。药理操作表明，同源配体5-羟色胺(5-HT)参与了RNA编辑的5-HT2C受体的调节。近交系小鼠在5-羟色胺和RNA编辑方面的差异暗示了变异的遗传来源。已知有两个单核苷酸多态影响小鼠的5-羟色胺能功能。目标1、2和3利用40个BXD小鼠重组近交系的平衡析因表，这些系代表SNPs TPH2：Pro447Arg和SLC6A4：Glu39Gly的每一个双等位基因组合。由于BXD RI系的遗传背景已通过育种随机化，这组小鼠实质上表现为色氨酸羟基酶和5-羟色胺转运体基因中两个重要功能SNPs的虚拟双同基因。目的1检测这些SNPs作为影响Htr2c RNA编辑谱的数量性状核苷酸(QTN)的候选能力。AIM 2使用全基因组QTL作图来更广泛地探索可能影响Htr2c RNA编辑图谱的其他遗传基因座。目的3探索Htr2c RNA编辑的行为和转录组相关性。小鼠大脑的研究区域是杏仁核，它富含5-HT2C受体，在压力、焦虑、恐惧和情绪学习和记忆中发挥重要作用。在人类中，杏仁核似乎在相关的心理障碍中发挥作用。5-羟色胺2C受体是心理健康研究的热点。这项建议旨在发现RNA变异的遗传原因和行为相关性，该RNA编码多达24种功能不同的5-羟色胺2C受体蛋白亚型。研究的大脑区域是杏仁核，它富含5-羟色胺2C受体，在焦虑症和抑郁症中起着重要作用。

DESCRIPTION (provided by applicant): Htr2c RNA editing alters the potential contribution of 5-HT2C receptors to brain function by producing up to 24 receptor isoforms with different signal transduction properties. Htr2c RNA editing is an important endophenotype for serotonergic function and psychiatric disease, and understanding the genetic etiology of this variation is an important goal. Pharmacological manipulations implicate the cognate ligand serotonin (5-HT) in the regulation of RNA edited 5-HT2C receptors. Inbred mouse strain differences in both serotonin and RNA editing implicate genetic sources of variation. Two single nucleotide polymoprhisms are known to affect serotonergic function in mice. Aims 1, 2, and 3 make use of a balanced factorial table of 40 BXD recombinant inbred lines of mice that represent every two-allele combination of the SNPs Tph2:Pro447Arg and Slc6a4:Glu39Gly. Because the genetic background of the BXD RI lines has been randomized by breeding, this panel of mice in essence performs as a virtual double congenic for two important functional SNPs in the genes for tryptophan hydroxylase and the serotonin transporter. Aim 1 tests the candidacy of these SNPs as quantitative trait nucleotides (QTNs) affecting Htr2c RNA editing profiles. Aim 2 uses genome-wide QTL mapping to explore more broadly other genetic loci that may influence Htr2c RNA editing profiles. Aim 3 proposes to explore behavioral and transcriptome correlates of Htr2c RNA editing. The mouse brain region of investigation is the amygdala, which is rich in 5-HT2C receptors and plays important functional roles in stress, anxiety, fear, and emotional learning and memory. In humans, the amygdala appears to function in related psychological disorders. The serotonin 2C receptor is a focus of mental health research. This proposal aims to discover genetic causes and behavioral correlates of variation in RNA that codes for up to 24 functionally different protein isoforms of the serotonin 2C receptor. The brain region of investigation is the amygdala, which is rich in serotonin 2C receptors and plays important roles in anxiety disorders and depression.