This SBIR project combines the use of genetic models with genomic, proteomic and metabolomic technologies as a solution to discover molecular fingerprints as biomarkers for alcohol-induced organ damage. While several classic biomarkers have been used by clinicians, there is no genetic or biochemical test that can: 1) reliably predict people predisposed to alcholism or the adverse effects of alcohol, 2) diagnose excessive alcohol use, or 3) predict disease pathogenesis. Knowledge gained from the genome sequencing projects combined with new genomic, proteomic and metabolomic technologies offers hope to clinicians that new biomarkers can be found. However, sample size issues, the lack of environmental control and uncontrolled genetic background effects makes starting with clinical samples difficult to decipher.Therefore, a need exists for reliable animal models to identify biomarkers. PhysioGenix is a leader in developing genetic models that can map quantitative trait loci (QTL) for complex human diseases and those that detect adverse drug responses. Our innovative approach to biomarker discovery leverages the power of these models as a way to reduce noise and simplify the complex fingerprints that clinicians will ultimately use for detecting people at risk or for patient care. First, we will determine whether a panel of chromosomal substitution strains (Consomic rats) can be used to genetically map QTLs for alcohol-related traits, like alcohol preference. The consomic panel has been constructed by introgressing """"""""normal"""""""" chromosomes from the Brown Norway rat onto the """"""""disease"""""""" background of the alcohol-prefering Fawn Hooded Hypertensive (FHH) rat. Second, we will measure the adverse response to different doses of ethanol in a genetically diverse but reproducible animal model, called the PharmGenix panel. The PharmGenix panel is validated as a way to measure organ damage to nephro- and hepatotoxins and can identify whether there are genetic components to toxicity. Third, we will test the ability of our genetic models to distinguish molecular fingerprints arising from the adverse response to alcohol. Deliverables from this Phase I project will be a gene expression fingerprint for alcohol-induced organ damage along with the proof that a genetic strategy is a key component to biomarker discovery programs. Phase II studies will expand the number of rat strains tested along with generating genomic, proteomic and metabolomic fingerprints from other organs. Importantly, we will validate the utility of several biomarkers by measuring their levels in patient samples. Relevance to public health: biomarkers will arm clinicians with the tools to predict individuals at risk for the effects of alcohol consumption and to track the progression of disease in patients.
