Determine the impact of canine MDR-1 mutations on therapeutic effectiveness and adverse reactions to veterinary drugs. These studies will improve CVM's ability to evaluate the safety of new animal drugs and create new models for investigation of possible adverse events. The pharmacogenomics data of a new drug and the potential for toxicity will improve the agency's ability to predict safety and effectiveness of canine new drugs. This project showcases the Office of Research's ability to connect several universally accepted experimental methodologies, from genetic analysis to computational modeling to traditional animal research, in order to discover therapeutically useful information. The ultimate outcome of this research will enhance CVM's ability to evaluate the safety and effectiveness of new animal drugs. Furthermore, CVM will be able to predict and hone in on adverse events more accurately. (1) ON TRACK ON TRACK main 1. Create genetically modified rodent expressing canine MDR-1 gene for evaluation as a model for pre-clinical testing of new veterinary pharmaceuticals 3/30/2010 Completed 3/30/2010 main 2. Genetically characterize MDR-1 gene in normal and affected collies, including response to drug treatments 4/30/2010 Completed 4/30/2010 main 3. Initiation of genetically modified rodent in-house breeding program 9/30/2010 Completed 9/30/2010 main 4. Initiation of validation study of genetically MDR-1 rodent model 10/30/2010 Completed 9/30/2010 main 5. Initiation of Collie Single Nucleotide Polymorphism (SNP) study analysis of MDR-1 gene in normal and affected collies 4/30/2011 Completed 4/30/2011 main 6. Analyze pharmacokinetics of two model drugs in normal and affected collies 9/30/2011 <i>(11/30/2011)</i> <i>(5/30/2012)</i> <i>(12/30/2012)</i> <i>(5/30/2013)</i> On Track main 7. Create a genetically modified rodent homozygous for the normal canine MDR-1 gene, for evaluating possible adverse events associated with veterinary pharmaceuticals 12/30/2011 Completed 12/30/2011 main 8. Publish manuscript for mouse model 12/30/2011 Completed 12/30/2011 main 9. Initiate cross-breeding of the two new rodent models to generate offspring that are heterozygous for the mutant canine MDR-1 gene 1/30/2012 Completed 1/30/2012 main 10. Validate a genetically modified mouse homozygous for the normal canine MDR-1 gene, for evaluating possible adverse events associated with veterinary pharmaceutical 6/30/2012 <i>(12/30/2012)</i> <i>(5/30/2013)</i> On Track main 11. Provide CVM reviewers with a mouse rodent that may be usd to replace the collies in safety assessments of new avermectin-class drugs for safety studies of other potential MDR-1 substrates 12/30/2012 <i>(12/30/2013)</i> Not Yet Started (1) The dates in italics under the milestone due dates are modified due dates which had to be updated due to real-time delays. The milestone status reflects the modified dates. MDR-1 Multidrug Resistance Protein 1 SNP genetic variation in a DNA sequence that occurs when a single nucleotide, or functional unit of DNA - a sugar group, is altered pharmacokinetics study of how the body processes a drug http://www.fda.gov/AboutFDA/Transparency/track/ucm203425.htm FDA-TRACK CVM Dashboard http://www.fda.gov/AnimalVeterinary/NewsEvents/FDAVeterinarianNewsletter/ucm222136.htm OR on the Cutting-Edge of Research - Biomarkers ਍††਍਍਍਍਍਍਍