Mouse models have proven very effective in clarifying our understanding of human disease. In particular, the development of mice bearing transgenes or mutations in which specific loci are silenced have lead to identification of novel pathways and mechanisms. During the past funding period, the use of knock-out mice has revealed the importance of IgM natural antibody and complement in induction of ischemia-reperfusion injury. The goal of the animal core in thecurrent proposal is to extend the studies by continuing to maintain and breed mice bearing specific deficiencies in C3, C4 and Cr2 and to generate new strains of mutant mice in which the immunoglobulin loci are modified using a gene targeting approach. Specifically, the animal core will establish transgenic (knock-in) mice in which a rearranged IgH (cm22Hi) and IgL (cm22Li) specific for ischemia antigen are inserted into the respective loci. In addition, mice bearing a mutation within the C/mu domain (IgM c1q-) will be established such that IgM no longer binds and activates Clq. IgM ctq- mice will be important in testing the hypothesis that IgM mediates ischemia-reperfusion injury via complement Clq. Both the complement deficient and the new strains of immunoglobulin mutant mice are critical for continuation of the study of thepathogenesis of I/R injury and will be shared among the different projects.In summary, the animal core not only provides novel strains of mice for extending our current studies on the biology of reperfusion -injury but also provides a critical link among the different projects of the Program Project.
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