Although steroids are highly effective in the control of asthma, some patients fail to respond even to high doses. Steroid resistance is a veritable health challenge due to the absence of therapeutic alternatives and a financial burden as steroid-resistant patients account for more than 50% of asthma-related healthcare costs. The awardee's research focuses on studying steroid resistance in airway smooth muscle (ASM), a tissue that is relevant for lung diseases. The short-term goal of the studies was achieved during the one-year mentored phase of the K99 award with the identification of some of the molecular mechanisms responsible for mediating IRF-1-induced inhibition of steroid function in ASM cells. Interestingly, decreasing IRF-1 levels restores only partially steroid responsiveness in cytokine-treated cells suggesting that pathways, other than IRF-1, could be involved in cytokine-induced steroid resistance and are the aims of, the studies under the ROD phase. Thus, the main goal of ROO award is to investigate the contribution of other inflammatory molecules in cytokine-induced steroid resistance with the ultimate objective to generate novel potential therapeutic options to treat steroid-resistant asthmatics. The central hypothesis of the ROO proposal is novel and states that pro-asthmatic cytokines impair steroid function in ASM cells through the coordinated activation of two IRF-1-independent pathways: (i) glucocorticoid receptor beta isoform (GRP), a steroid receptor beta isoform that can act as an inhibitor of GC actions (will be addressed in Aim 1), and (ii) Serine/threonine protein phosphatase 5 (PP5), shown to act as an inhibitor of steroid actions in different cell lines (will be addressed in Aim 2). These latter two aims of the present proposal will rely on multiple complementary approaches such as siRNA technology, transfection of reporter vectors as well as overexpression of constitutively active or dominant negative proteins, co-immunoprecipitation and co-locaiization techniques, chromatin immunoprecipitation and gel shift assays. Subsequently, this award will dramatically strenghten the applicant's independence, will broaden his expertise in molecular pharmacology and cell biology, and importantly will yield high quality data necessary for his projected R01 application.
I believe that this proposal is relevant to public health since improving our knowledge about the mechanisms leading to steroid resistance will help design new therapeutic alternatives to treat asthmatics who are resistant to steroid therapy.
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