Genetics of In-Stent Restenosis: The Mouse to Human Strategy

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DESCRIPTION (provided by applicant): This application aims to develop the candidate's expertise in mammalian genetics and achieve independent status as an investigator in cardiovascular diseases. The minority candidate is a non-tenured Assistant Professor at the University of Miami with a solid training and foundation in vascular and molecular biology. The candidate will proceed with outstanding institutional support and the work will be performed under the mentorship of recognized leaders in genetics, bioinformatics, and clinical and basic vascular biology. The overall objective of the current inter-disciplinary project is to utilize the best-in-class animal model to characterize the genetic determinants of in-stent restenosis (ISR) using a mouse-to-human ('forward genetics) strategy. The use of inbred mice as a model for human disease is appropriate given both exhibit predispositions to common complex vascular disorders such as atherosclerosis and restenosis; and the mouse and human genomes are closely related facilitating translation. We hypothesize that differences in in- stent restenosis among inbred strains of mice are due to genetic variations and that these polymorphic genes can be identified through genome-wide association and linkage mapping in mice. We will use bare metal stents and monitor multiple relevant well-accepted ISR endpoints in at least 22 genetically diverse inbred strains whose genotypes are publicly available on over 7 million single nucleotide polymorphisms. We will determine the number and location of quantitative trait loci among inbred strains with different phenotypes that characterize susceptibility to ISR. We will develop a preliminary genome-wide haplotype association map. In further studies we will confirm and fine mapping linkage in F2 combined crosses. Herein, we will prioritize the analysis of candidate genes underlying these susceptibility loci by starting with those where concordance is demonstrated with human data, and/or on the basis of known function in vascular, inflammatory, or proliferative disorders. With the successful conclusion of these studies, we expect to provide an unbiased assessment of genetic susceptibility to ISR that may aid gene candidate identification, biomarker development, and facilitate similar studies in humans. We also expect to provide a foundation for a series of highly competitive NIH grants that will extend our findings of genetic risk factors to the discovery of drug targets for ISR in high-risk individuals. RELEVANCE (See instructions): In-stent restenosis is the major complication that occurs in 5-25% of cases of percutaneous coronary interventions, the highly effective way to unblock coronary arteries and facilitate coronary revascularization. Identifying the genomic risk factors for in stent restenosis represent a breakthrough that provides new therapeutic strategies and targets to prevent these complications and save lives. (End of Abstract)