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.
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