Overproduction of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) has been implicated in the? pathogenesis of airway inflammation of asthma. The long-term goal of this research is to understand the? regulation of iNOS activity and to devise novel methods to regulate it. Although much is known about? factors affecting the synthesis and catalytic activity of iNOS, little is known about its cellular regulation. We? have recently shown that iNOS is degraded through the ubiquitin-proteasome pathway. The specificity of? the ubiqutination system is mainly provided by the specific ubiquitin ligase enzyme (E3) that recognizes and? binds to the target protein. Our preliminary data identified an F-box-containing protein; we termed UBLinos? that is a likely candidate to be the E3 ubiquitin ligase for iNOS. Additional preliminary data suggest that cells? regulate NO synthesis by temporal and spatial regulation of iNOS. These mechanisms include a relatively? rapid rate of iNOS turnover and sequestration of iNOS to a perinuclear location we termed the """"""""physiologic? aggresome."""""""" Furthermore, we have recently discovered that a specific class of imidazole like compounds? acts by co-translational inhibition of iNOS assembly. Thus, the use of these compounds represents a? specific and an efficient method to inhibit iNOS production.? We propose to test the following hypotheses: A) An F-box-containing protein (UBLinos) is the E3 ligase for? iNOS and it plays a central role in iNOS cellular regulation. B) The cellular temporal and spatial regulation? of iNOS plays a critical role in the observed upregulation of iNOS associated with airway inflammation.? iNOS translational inhibitors will reduce iNOS levels and ameliorate inflammation in experimental mouse? models of asthma. To test these hypotheses we propose studies with the following specific aims: 1)? Determination of mechanisms of iNOS regulation by UBLinos. 2) Elucidation of the cellular temporal and? spatial regulation of iNOS in airway inflammation. 3) Evaluation of the use of iNOS translational inhibitors in? experimental asthma by testing their effects in mouse models of asthma. The above studies will be done in? cultured cells as well as in primary cells obtained from normal subjects, patients with asthma and from? mouse models of asthma. The results of these studies will enhance our understanding of the regulation of? NO synthesis by iNOS in airway inflammation and lay the groundwork for therapeutic strategies aimed at? regulating iNOS in such disorder.?
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