In vivo systems level analysis of gene-environment interactions

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DESCRIPTION (provided by applicant): This RC4 application addresses three Thematic Areas. Thematic Area #1, Applying Genomics and Other High-Throughput Technologies, calls for major advances in the understanding of the mechanisms of diseases through the use of DNA sequencing, microarray technology, new imaging modalities, and computational biology. Thematic Area #2, Translating Basic Science Discoveries into New and Better Treatments, challenges the research community to develop new diagnostic and therapeutic strategies via high-throughput screening. Thematic Area #5, Reinvigorating the Biomedical Research Community, calls for new and innovative multi-disciplinary collaborations to solve the most challenging biomedical and behavioral issues. The proposed project will address these Thematic Areas by creating an automated high-throughput rapid- assessment zebrafish laboratory in which researchers can explore the interactions among genes, chemicals, and diseases. This laboratory will expose at least 10,000 zebrafish per day to chemicals from libraries and observe their behavioral and anatomical responses. When the chemicals evoke a response, researchers will exploit unique genomic tools to elucidate the sequence of events that led to it. They will thereby gain a mechanistic understanding of the zebrafish's response to the chemical and also identify the biomolecular networks that sustain life or result in pathology. Compared with analogous studies in rodents, the high- throughput facility will reduce the cost by four orders of magnitude and the duration by two orders of magnitude. The proposed project will increase the throughput of the zebrafish facility at the Sinnhuber Aquatic Research laboratory by increasing the rates of embryo production and handling, the capacity of the specific- pathogen-free water system, automating behavioral and histological endpoints, and the throughput for genomic, metabolomic, and epigenetic analyses. The proposed facility will be the first institution capable of supporting high-throughput studies of the interactions among genes, chemicals, and diseases in the developmental context of a whole vertebrate. It will serve equally well the interests of toxicologists exploring the impact of an environmental stressor, pharmacologists developing a new drug, and geneticists wanting to identify the function and interactions of an unknown gene. The proposed high-throughput facility will serve as the Rosetta Stone of modern genomic research. It will deliver fast and inexpensive techniques for elucidating biomolecular networks in zebrafish. The research community will translate this knowledge to decipher the workings of the human genome and its interactions with the environment. PUBLIC HEALTH RELEVANCE: Research conducted at this high-throughput facility will generate mechanistic understanding of the relationships among genes, chemicals, and diseases and thereby generate useful hypotheses and targets for novel therapeutic interventions. This work will lead to better ways of preventing, treating, and curing diseases. By dramatically reducing the cost and the time required to conduct mechanistic toxicology studies, the facility will make it economically feasible to test for toxicity all of 70,000 chemicals to which commercial products expose the American public. Current procedures evaluate only about 60 chemicals a year.