Genetic analysis of Htr2c RNA editing in amygdala

杏仁核 Htr2c RNA 编辑的遗传分析

• 批准号: 7257336
• 负责人: DAVID C AIREY
• 金额: $ 23.89万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-15 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7257336
• 关键词: 5-Hydroxytryptophan; Affect; Alleles; Amygdaloid structure; Anxiety; Anxiety Disorders; Behavior; Behavioral; Biological Markers; Brain; Brain region; Breeding; Code; Collaborations; Complex Genetic Trait; Computer Simulation; Data; Development; Doctor of Philosophy; Emotional; End Point; Ensure; Equilibrium; Fright; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Markers; Genetic Predisposition to Disease; Genetic screening method; Genome; Genome Scan; Goals; Grant; Human; Hydroxyindoleacetic Acid; Inbred Strain; Inbred Strains Mice; Investigation; Joints; Laboratories; Learning; Ligands; Maps; Measurement; Measures; Memory; Mental Depression; Mental Health; Mental disorders; Metabolism; Methods; Mus; Nucleotides; Other Genetics; Paper; Phenotype; Play; Property; Protein Isoforms; Publishing; Quantitative Trait Loci; RNA; RNA Editing; Randomized; Recombinants; Regulation; Research; Role; Serotonin; Serotonin Receptor 5-HT2C; Signal Transduction; Site; Source; Stress; Surveys; Synapses; Testing; Tryptophan 5-monooxygenase; Variant; base; congenic; endophenotype; genetic analysis; receptor; serotonin transporter; trait; virtual

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.

描述（由申请人提供）：ht2c 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受体对脑功能的潜在贡献。Htr2c RNA编辑是血清素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。药理学操作涉及同源配体5-羟色胺（5-HT）在RNA编辑的5-HT2C受体的调节。近交系小鼠血清素和RNA编辑的差异暗示了变异的遗传来源。已知两个单核苷酸多态性影响小鼠血清素能功能。目的1、2和3利用了40个BXD重组小鼠自交系的平衡因子表，这些自交系代表了SNPs Tph2:Pro447Arg和Slc6a4:Glu39Gly的每一个双等位基因组合。由于BXD RI系的遗传背景是通过育种随机化的，因此这组小鼠本质上是色氨酸羟化酶和血清素转运蛋白基因中两个重要功能snp的虚拟双同源基因。目的1测试这些snp作为影响Htr2c RNA编辑谱的数量性状核苷酸（QTNs）的候选性。Aim 2使用全基因组QTL定位来更广泛地探索可能影响Htr2c RNA编辑谱的其他遗传位点。目的3提出探索Htr2c RNA编辑的行为和转录组相关因素。研究的小鼠大脑区域为杏仁核，杏仁核富含5-HT2C受体，在应激、焦虑、恐惧和情绪学习记忆中起重要的功能作用。在人类中，杏仁核似乎在相关的心理疾病中起作用。血清素2C受体是心理健康研究的焦点。本研究旨在发现编码多达24种功能不同的5 -羟色胺2C受体蛋白亚型的RNA变异的遗传原因和行为相关性。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重要作用。