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: 7677521
• 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
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7677521
• 关键词: Affect; Amaze; Antidepressive Agents; Anxiety; Architecture; Autistic Disorder; Behavior; Behavioral Assay; Brain; Chronic; Circadian Rhythms; Collaborations; Complex; Depth; Dorsal; Enzymes; Equilibrium; Fee-for-Service Plans; Gene Expression Profile; Genes; Genetic; Genetic Variation; Genotype; Inbred Mouse; Inbred Strains Mice; Laboratories; Link; Measures; Mental Depression; Microarray Shared Resource; Midbrain structure; Modeling; Molecular; Motor Activity; Mouse Strains; Mus; Pattern; Pharmaceutical Preparations; Pharmacology; Phenotype; Pliability; Population; Principal Investigator; Production; Protein Isoforms; Proteins; RNA Editing; Randomized; Rate; Rattus; Recombinants; Research Personnel; Resources; Sampling; Seeds; Selective Serotonin Reuptake Inhibitor; Serotonin; Signal Transduction; Single Nucleotide Polymorphism; Standards of Weights and Measures; Surveys; System; Systems Analysis; Systems Biology; TDO2 gene; Thinking; Tryptophan 5-monooxygenase; Tryptophanase; Variant; biobehavior; design; dorsal raphe nucleus; drug discrimination; endophenotype; extracellular; 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，支持小鼠血清素能表型的遗传变异，Sanders-Bush和 同事们利用重组近交（RI）菌株中存在的遗传和表型变异， 小鼠照亮5 HT基因网络，为5 HT信号传导、行为和药物提供动态灵活性 应答影响多巴胺能信号传导能力的两种关键蛋白质是脑色氨酸羟化酶 （TPH 2），用于产生脑5 HT的限速酶，和血清素转运体（SERT）， 负责突触前再摄取胞吐的5 HT。在C57 BL/6 J和DBA/2 J标准自交系中， 在小鼠品系中，单核苷酸多态性存在于脑TPH（Tph 2）基因和脑TPH（Tph 2）基因中。 SERT基因（Slc 6a 4）。证据支持这些等位基因变体编码的蛋白质的功能改变， 激发了对它们的组合作用的进一步体内研究。筛选出40个BXD重组自交系 在随机化的C57 BL/6 J和DBA/2 J遗传背景上， Tph 2和Slc 6a 4中的功能性SNP。这种平衡析因设计支持估计加性或 这些SNP对5-HT连锁的内表型（目的1）和行为（目的2）的上位作用模式，以及 用于种子和约束更全面的中缝背核转录组的系统建模 遗传学方法（目标3）。目的1询问Tph 2和Slc 6a 4基因型是否改变了一套5 HT测量， 包括5-HT水平和SERT功能，5-HT周转和细胞外5-HT水平，以及5-HT水平和 5 HT 1A、5 HT 2A和5 HT 2C受体的功能。目的2询问Tph 2和Slc 6a 4基因型是否预测 焦虑、抑郁和SSRI反应的多种行为，被认为是自闭症特征的模型， 和昼夜节律行为。目的3确定Tph 2中功能性SNP的慢性转录组应答 和Slc 6a 4，并将进一步描述与这些SNP相关的内部验证的基因网络模型 以及目标1和2所述的表型。基因编码中功能性SNP的存在 影响5 HT信号传导能力的关键蛋白质，以及Conte同事的综合专业知识， n前所未有的机会，整合我们对潜在的 5 HT信号的分子架构，探索控制5 HT的网络和系统 在复杂的遗传背景下组装和发挥作用。