Project 4 Genetic Variation of Murine Serotonergic Phenotypes

项目 4 小鼠血清素能表型的遗传变异

• 批准号: 7921656
• 负责人: ELAINE SANDERS BUSH
• 金额: $ 22.48万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7921656
• 关键词: Affect; Amaze; Antidepressive Agents; Anxiety; Architecture; Autistic Disorder; Behavior; Behavioral Assay; Brain; Chronic; Circadian Rhythms; Collaborations; Complex; Dorsal; Enzymes; Equilibrium; Fee-for-Service Plans; Gene Expression Profile; Genes; Genetic; Genetic Variation; Genotype; Inbred Mouse; Inbred Strains Mice; Laboratories; Link; Measures; Microarray Shared Resource; Midbrain structure; Modeling; Molecular; Motor Activity; Mouse Strains; Mus; Pattern; Pharmaceutical Preparations; Pharmacology; Phenotype; Population; Principal Investigator; Production; Protein Isoforms; Proteins; RNA Editing; Randomized; Rattus; Recombinants; Research Personnel; Resources; Sampling; Seeds; Selective Serotonin Reuptake Inhibitor; Serotonin; Signal Transduction; Single Nucleotide Polymorphism; Surveys; System; Systems Analysis; Systems Biology; TDO2 gene; Tryptophan 5-monooxygenase; Variant; biobehavior; depression; design; dorsal raphe nucleus; drug discrimination; endophenotype; extracellular; flexibility; gene interaction; in vivo; mouse genome; network models; presynaptic; programs; protein function; receptor; response; reuptake; serotonin transporter; synaptic function; trait; transcriptomics

In Project 4, Genetic Variation in Support of Murine Serotonergic Phenotypes, Sanders-Bush and colleagues take advantage of genetic and phenotypic variation present in recombinant inbred (Rl) strains of mice to illuminate 5HT gene networks that provide for dynamic flexibility in 5HT signaling, behavior and drug responses. Two critical proteins affecting serotonergic signaling capacity are brain tryptophan hydroxylase (TPH2), the rate-limiting enzyme for the production of brain 5HT, and the serotonin transporter (SERT), responsible for presynaptic reuptake of exocytosed 5HT. In the C57BL/6J and DBA/2J standard inbred strains of mice, a single nucleotide polymorphism is present in both the gene for brain TPH (Tph2) and the gene for SERT (Slc6a4). Evidence supports altered function of the proteins encoded by these allelic variants, motivating further in vivo study of their combined effects. We have selected 40 BXD recombinant inbred lines to represent, on a randomized C57BL/6J and DBA/2J genetic background, every allelic combination of the functional SNPs in Tph2and Slc6a4. This balanced factorial design supports the estimation of additive or epistatic modes of action of these SNPs on 5HT linked endophenotypes (Aim 1) and behaviors (Aim 2), and serves to seed and constrain more comprehensive modeling of the dorsal raphe transcriptome by systems genetics approaches (Aim 3). Aim 1 asks if Tph2 and Slc6a4 genotype alters a suite of 5HT measures, including levels of 5HT and function of SERT, 5HT turnover and extracellular levels of 5HT, and levels and function of 5HT1A, 5HT2A, and 5HT2C receptors. Aim 2 asks if Tph2 and Slc6a4 genotype predicts multiple behaviors for anxiety and depression and SSRI response, behaviors thought to model autism traits, and circadian behavior. Aim 3 determines the chronic transcriptome response to functional SNPs in Tph2 and Slc6a4, and further will describe internally validated gene network models correlated with these SNPs and the phenotypes described by Aims 1 and 2. The presence of functional SNPs in genes encoding critical proteins affecting 5HT signaling capacity, and the combined expertise of Conte colleagues, provides n unprecedented opportunity to integrate our in-depth understanding of the underlying olecular architecture of 5HT signaling into an exploration of networks and systems that control 5HT assembly and function in a complex genetic background.

在项目4中，支持鼠血清素能表型，Sanders-Bush和 同事利用重组近交（RL）菌株中存在的遗传和表型变异的优势 小鼠照亮5HT基因网络，可在5HT信号，行为和药物中提供动态灵活性 回答。两种影响血清素能信号能力的关键蛋白是脑色氨酸羟化酶 （TPH2），用于生产脑5HT的速率限制酶，以及5-羟色胺转运蛋白转运蛋白（SERT）， 负责外旋转5HT的突触前再摄取。在C57BL/6J和DBA/2J标准INBRED中 小鼠菌株，单个核苷酸多态性在脑TPH（TPH2）和 Sert的基因（SLC6A4）。证据支持这些等位基因变体编码的蛋白质功能的改变， 激励进一步的体内研究其综合作用。我们选择了40个BXD重组近交系 为了代表随机的C57BL/6J和DBA/2J遗传背景，每个等位基因组合 TPH2和SLC6A4中的功能性SNP。这种平衡的阶乘设计支持添加剂的估计或 这些SNP对5HT连接的内表型（AIM 1）和行为（AIM 2）和 通过系统播种和限制背侧Raphe转录组的更全面的建模 遗传学接近（目标3）。 AIM 1询问TPH2和SLC6A4基因型是否改变了5HT度量的套件， 包括SERT的5HT和功能的水平，5HT的周转率和5HT的细胞外水平以及水平以及 5HT1A，5HT2A和5HT2C受体的功能。 AIM 2询问TPH2和SLC6A4基因型是否预测 焦虑和抑郁和SSRI反应的多种行为，被认为是自闭症特征的行为， 和昼夜行为。 AIM 3确定TPH2中对功能SNP的慢性转录组响应 和SLC6A4，并进一步描述与这些SNP相关的内部验证基因网络模型 和目标1和2所描述的表型。编码基因的功能SNP的存在 影响5HT信号能力的关键蛋白质以及孔戴同事的联合专业知识提供 n前所未有的机会，可以整合我们对基础的深入理解 5HT信号传导的卵形结构，以探索控制5HT的网络和系统 组装和功能在复杂的遗传背景中。