Project 4 Genetic Variation of Murine Serotonergic Phenotypes

项目 4 小鼠血清素能表型的遗传变异

基本信息

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
项目类别：
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

项目摘要

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，支持小鼠血清素表型的遗传变异，Sanders-Bush 和同事们利用重组近交（Rl）菌株中存在的遗传和表型变异小鼠阐明 5HT 基因网络，为 5HT 信号、行为和药物提供动态灵活性回应。影响血清素信号传导能力的两种关键蛋白质是脑色氨酸羟化酶 (TPH2)，大脑 5HT 产生的限速酶，以及血清素转运蛋白 (SERT)，负责突触前再摄取胞吐的 5HT。在C57BL/6J和DBA/2J标准近交系中在小鼠品系中，脑 TPH (Tph2) 基因和 SERT 基因（Slc6a4）。有证据支持这些等位基因变体编码的蛋白质功能发生改变，激发进一步体内研究其综合作用。我们精选了40个BXD重组自交系代表，在随机 C57BL/6J 和 DBA/2J 遗传背景上，每个等位基因组合 Tph2 和 Slc6a4 中的功能性 SNP。这种平衡因子设计支持加性或这些 SNP 对 5HT 相关内表型（目标 1）和行为（目标 2）的上位作用模式，以及用于通过系统播种和限制中缝背侧转录组的更全面的建模遗传学方法（目标 3）。目标 1 询问 Tph2 和 Slc6a4 基因型是否改变了一套 5HT 测量值，包括 5HT 水平和 SERT 功能、5HT 周转和 5HT 细胞外水平，以及 5HT1A、5HT2A 和 5HT2C 受体的功能。目标 2 询问 Tph2 和 Slc6a4 基因型是否预测焦虑和抑郁的多种行为以及 SSRI 反应，被认为可以模拟自闭症特征的行为，和昼夜节律行为。目标 3 确定 Tph2 中功能性 SNP 的慢性转录组反应和 Slc6a4，并进一步描述与这些 SNP 相关的内部验证的基因网络模型以及目标 1 和 2 所描述的表型。编码基因中功能性 SNP 的存在影响 5HT 信号传导能力的关键蛋白质，以及 Conte 同事的综合专业知识，提供了 n 前所未有的机会来整合我们对底层的深入理解 5HT 信号传导的分子结构探索控制 5HT 的网络和系统在复杂的遗传背景下组装和发挥作用。