Tim Wiltshire - US grants

[unreadable] 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. [unreadable] [unreadable] [unreadable]

The devastating effects of drug addiction on the lives of those who struggle with it, and the social and economic implications for society as a whole are staggering. Faced with this challenge, understanding the biological pathways that predispose individuals to addiction to cocaine (and other drugs) is a top priority in the research community. Genetic background is thought to influence an individual's predisposition to abuse drugs and this hypothesis is supported by studies in animal models, by clinical observations in humans, and by animal studies showing mouse inbred strain differences in behaviors that model addiction liability. While no animal model exists that recapitulates the entire spectrum of the drug abuse syndrome in humans, animal models do exist to examine specific drug[unreadable]related behaviors. Locomotor response to drug administration models initial sensitivity to the stimulant effects of the drug. Rodents that exhibit increased locomotor response to psycho stimulants also show faster rates of acquisition in drug self[unreadable]administration assays, which suggests that initial sensitivity to cocaine predicts liability to addiction. The goal of this proposal is to identify genetic loci involved in the regulation of cocaine locomotor response as an indication of drug sensitivity. Our strategy takes advantage of naturally occurring phenotypic variation between inbred mouse strains and haplotype association mapping, a genetic approach for mapping complex trait genes. In addition, gene expression paHerns in brain regions involved in drug response and addiction as well as pharmacokinetic properties of cocaine will be examined across strains to identify gene expression and pharmacokinetic differences that may contribute to phenotypic variation.

DESCRIPTION (provided by applicant): Important progress continues to be made in the treatment of most common cancers, but therapeutic benefit remains difficult to predict and severe or fatal adverse events occur frequently. The Human Genome Project has fueled the notion that genetic information can produce effective and cost-efficient selection of therapies for individual patients, but validated genetic signatures that predict response to most chemotherapy regimens remain to be identified. Numerous genes potentially influence drug response, but current candidate-gene approaches are limited by the requirement of a priori knowledge about the genes involved and the moderate size of most clinical trials often limits the power of in vitro genome wide association studies (GWAS) for cancer pharmacogenomics discovery. In response to these limitations, we have undertaken a thorough, pharmacogenomic assessment of cytotoxic effect of the majority of FDA approved anti-cancer compounds using an ex vivo model system to determine the heritability of drug-induced cell killing to prioritize drugs for pharmacogenomic mapping. These results are an important first step, and while high heritability of a trait does not guarantee successful association mapping results, it represents an important first step and the results will be used to prioritize drugs with high heritabilities for genome-wide association mapping. In the current proposal, GWAS mapping of cytotoxic agents will be performed in a European American population, and then replication GWAS mapping will be performed in an East Asian population. In addition to discovering and validating genetic variants that predict drug response, the wealth of data collected will be used to dissect the underlying etiology of drug response traits, including assessing the relative contribution of genetic, environmental, and interaction components of variation. These results will provide crucial insight to prioritize genetic variants for follow-up in precious clinical population resources, and potentially reveal new insight into the overall etiology of drug responses.