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Biochemistry of leukotrienes, inflammatory and allergic mediators in the arachidonic acid cascade


The objectives of the present project are to study cellular and molecular mechanisms of leukotriene biosynthesis. The work is divided into two major sections, i.e. 1. Structure and function of enzymes in leukotriene biosynthesis, and 2. Cellular regulation of enzyme activities and gene expression. Consequently, it will address the issues of activation, maintenance and regulation of the cascade with the ultimate goal to understand and gain control of the biosynthetic machinery.

Leukotrienes, a family of paracrine hormones within the arachidonic acid cascade, are regarded as powerful chemical mediators of allergic and inflammatory reactions. Several lines of evidence point to a crucial role of leukotrienes in the pathophysiology of respiratory problems and asthma. Hence, to control the biosynthesis and actions of leukotrienes is one important therapeutic strategy in the treatment of asthma and related inflammatory and allergic diseases.

An important effort will be made to characterize, at a molecular level, central enzymes and other cellular factors involved in leukotriene biosynthesis. This work includes enzyme purification and characterization, molecular cloning of both cDNAs and genomic sequences, gene promoter characterization, expression of recombinant enzymes, and site-directed mutagenesis. Detailed information on functional elements and catalytic mechanisms of individual enzymes is expected to be instrumental for the design of more potent and specific enzyme inhibitors, which can be developed into novel anti-asthmatic drugs. Using cellular models of leukotriene biosynthesis, expression of enzyme activity, protein and mRNA will be studied and the potential effects of post-translational modification of enzymes, cytokines, degree of cellular differentiation/maturation and cell-cell interactions. In particular, factors which determine gene transcription will be identified and characterized at a molecular level. A thorough understanding of regulatory mechanisms involved in cellular leukotriene biosynthesis, including factors of pathophysiological significance as well as novel potential targets for pharmacological intervention.

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9,Doktorsringen 9 A

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