Leukotrienes are potent modulators of inflammatory processes. Leukotrienes have been demonstrated to play a role in a number of disease and recent evidence suggests that they are also involved in graft rejection. We propose to evaluate the role of these compounds in renal allograft rejection. The initial step in achieving this goal will be the generation of mice with mutations in the genes encoding essential enzymes in the leukotriene biosynthetic pathway. Use of these mouse strains as both recipients and donors of renal allografts should allow a comprehensive evaluation of the role of leukotrienes in the initiation and progression of graft destruction. Our approach to the production and characterization of these mouse strains can be divided into four specific aims: 1. Generation of mice unable to synthesize all leukotrienes. The genes for both the FLAP and 5LO will be disrupted in ES cells and the resulting ES cells and the resulting ES cell lines will be used to mice homozygous for this mutation. 2. Generation of mice unable to synthesis LTB4. Leukotrienes produced from arachidonic acid can be divided based on biological activities into two subgroups: 1) LTB and 2) the cysteinyl leukotrienes. To define the biological roles of each of these subgroups we will disrupt LT4 hydroxylase, an enzyme responsible for the biosynthesis of LTB4 and LTA4. Results obtained from LTB4 and LTA4 deficient animals will allow us to better define the role that these subgroups plays in renal graft functioning. 3. Analysis of animals defective in the production of leukotrienes. The effect of each mutation on leukotriene production will be verified. Animals will be examined for any alteration in development or function of immunological cell populations. 4. Effect of loss of leukotriene production on the renal transplant function. We will examine the role of leukotrienes as intermediates of cyclosporin toxicity and in the rejection of the graft by the host immune system.
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