Project 2 will use a newly developed model of myocardial ischemia and reperfusion in the mouse to take advantage of genetic techniques which allow development of mutant mice with deficiencies of selected genes by the process of targeted homologous recombination in embryonic stem cells. This technique allows for the development of mice with either a total deficiency of a gene product or a tissue specific absence. This molecular genetic approach will complement in vivo studies and in vitro studies in Projects 1 and 3, which have relied very heavily on monoclonal antibodies to dissect out the roles of various adhesion molecules and cytokines in the inflammatory process. Reperfusion markedly accelerates the development of an inflammatory reaction in the infarcted tissue that might cause injury acutely but might facilitate healing and reduce remodelling of the ventricle chronically. The following specific aims are proposed: 1). Continuation of characterization of the mouse model of myocardial ischemia - reperfusion with respect to quantitation of infarct size, leukocyte trafficking, cytokine induction, and adhesion molecule expression. 2) Development and characterization mutant mice deficient in CD11a and CD11b. 3). Utilization of mice with specific genetic deficiencies in the model of ischemia reperfusion with assessment of infarct size, leukocyte trafficking, and induction of cytokines and adhesion molecules. 4). Examination of ventricular healing and remodeling after myocardial ischemia with and without reperfusion in the normal mouse as compared to mice with genetic deficiencies in molecules that are important in leukocyte extravasation, neutrophil mediated myocyte injury, and neutrophil chemotaxis and activation. Mouse models are being widely used to define the roles of specific genes in cardiovascular disease. In addition to being well defined immunologically and amenable to genetic manipulation, the mouse has a short gestation time and it is possible to perform a large number of experiments with inbred mice. Mutant mice will be utilized to determine the role of specific genes in the cell biology of both the acute inflammatory process and the more chronic healing and remodeling which occurs after myocardial ischemia with and without reperfusion.
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