Organismal, Cellular, and Genetic Networks in Anxiety and Depression

焦虑和抑郁中的有机体、细胞和遗传网络

基本信息

批准号：
7683711
负责人：
Tim Wiltshire
金额：
$ 31.31万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-03 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7683711
关键词：
Adrenal Glands Algorithms Amygdaloid structure Animal Model Animals Antibodies Anxiety Behavior Behavioral Behavioral Assay Biochemical Biochemical Genetics Biochemical Markers Biological Assay Biological Markers Brain Brain region Candidate Disease Gene Chronic Complex Computer Simulation Data Data Set Development Diagnosis Disease Disease Marker Disease model Economic Burden Environmental Risk Factor Enzyme-Linked Immunosorbent Assay Female Fluoxetine Foundations Gene Expression Gene Expression Profiling Genes Genetic Genetic Polymorphism Genome Genomics Genotype Goals Haplotypes Harvest Hippocampus (Brain)Home environment Human Hypothalamic structure Inbred Strain Inbred Strains Mice Individual Label Link Maps Measurement Measures Methodology Methods Mouse Strains Mus Pattern Pharmaceutical Preparations Pharmacogenomics Phenotype Pituitary Gland Principal Investigator Process Protocols documentation Quantitative Trait Loci RNA Regulatory Pathway Research Personnel Sampling Series Serum Stress Tests Suspension substance Suspensions Swimming Symptoms Tail Suspension Testing Thyroid Gland Tissues Translating Ursidae Family Validation Variant acute stress base behavior measurement behavior test depression depressive symptoms disability dorsal raphe nucleus frontal lobe genetic analysis genetic association high throughput screening human disease insight male mouse genome mouse model programs remediation research study treatment effect

项目摘要

DESCRIPTION (provided by applicant): Depression and anxiety are serious disorders that contribute to both individual disability and high economic burden. There are a broad spectrum of symptoms, diagnoses and treatments for both, and a wide range of factors that may contribute to episodes of disease. Animal models have been extensively used to try and delineate the genes involved, the confounding environmental factors, and validation of drug treatments for both anxiety and depression. Our long term goal is to define new genetic components and biochemical interactions that are key to the development of anxiety and depression. The overall hypothesis is that we can identify genetic components that contribute to disease states, or in fact treatments, of anxiety and depression, by using multiple inbred mouse strains. We have recently developed new methods to define associations between haplotype and phenotype: in silico quantitative trait loci (QTLs). The underlying prerequisite for this approach is that the inbred mouse strains show marked phenotypic differences and multiple studies have shown this to be the case. Based on these observations we propose to measure behavioral differences, levels of relevant biochemical markers, and whole-genome gene expression levels in appropriate tissues across thirty inbred mouse strains. These phenotypic data will enable a comprehensive characterization of depression and anxiety through genetic association studies on biochemical, cellular, and behavioral levels. Furthermore, our findings in mouse models will be translated to human disease relevance through candidate gene sequencing and pharmacogenomic studies. The specific aims are: 1) Identify QTL associated with behavioral differences in multiple inbred strains. We will collect data for seven behavioral assays shown to measure aspects of anxiety and depression 2) Develop multiplexed sets of assays for biochemical markers for QTL mapping studies. Up to 15 multiplexed biochemical markers associated with anxious or depressive phenotypes will be developed for measurement of basal analyte levels. 3) Characterize genetic regulatory pathways using gene expression profiling in relevant tissues over multiple strains. Whole genome gene-expression analysis will be performed across strains for seven tissues. 4) Assess the relevance of inbred strain mouse models using candidate gene sequencing and pharmacogenomic profiling. Candidate genes identified from the multi-phenotype genetic analysis of mouse strains will be tested for polymorphisms that could be associated with disease. In addition, a drug fluoxetine, will be administered to mice to modulate basal level phenotypic measurements to track perturbations at the biochemical, genetic and organismal level.

描述（由申请人提供）：抑郁症和焦虑症是严重的疾病，会导致个人残疾和沉重的经济负担。两者都有广泛的症状、诊断和治疗，以及可能导致疾病发作的多种因素。动物模型已被广泛用于尝试和描述所涉及的基因、混杂的环境因素以及对焦虑和抑郁药物治疗的验证。我们的长期目标是定义新的遗传成分和生化相互作用，它们是焦虑和抑郁发展的关键。总体假设是，我们可以通过使用多种近交小鼠品系来识别导致疾病状态或实际上治疗焦虑和抑郁的遗传成分。我们最近开发了新方法来定义单倍型和表型之间的关联：计算机数量性状基因座（QTL）。这种方法的基本先决条件是近交系小鼠品系表现出明显的表型差异，多项研究表明情况确实如此。基于这些观察，我们建议测量三十个近交系小鼠品系的行为差异、相关生化标记物的水平以及适当组织中的全基因组基因表达水平。这些表型数据将通过生化、细胞和行为水平的遗传关联研究来全面表征抑郁和焦虑。此外，我们在小鼠模型中的发现将通过候选基因测序和药物基因组学研究转化为人类疾病的相关性。具体目标是： 1) 鉴定与多个近交系行为差异相关的 QTL。我们将收集七种行为测定的数据，用于测量焦虑和抑郁的各个方面。 2) 开发用于 QTL 作图研究的生化标记的多重测定。将开发多达 15 种与焦虑或抑郁表型相关的多重生化标记物，用于测量基础分析物水平。 3) 使用多个菌株相关组织中的基因表达谱来表征遗传调控途径。将针对七个组织的菌株进行全基因组基因表达分析。 4) 使用候选基因测序和药物基因组分析评估近交系小鼠模型的相关性。对小鼠品系的多表型遗传分析中鉴定出的候选基因将进行可能与疾病相关的多态性测试。此外，还将向小鼠施用药物氟西汀以调节基础水平表型测量，以跟踪生化、遗传和有机体水平的扰动。