G-protein coupled receptor kinase-5 (GRK5) is a member of the GRK family of kinases, originally discovered in the context of G-protein coupled receptor (GPCR) desensitization. Recent studies from our lab and others have demonstrated critical role of GRK5 in inflammatory pathways particularly involving Toll-like receptors. Because Toll-like receptor signaling pathways are critical in the regulation of sepsis pathogenesis, it was hypothesized that GRK5 is a critical regulator of inflammatory pathways in sepsis pathogenesis. Thus the overall goal of the thesis project was to decipher the role of GRK5 in sepsis pathogenesis using mouse models of sepsis. In initial studies, we demonstrated GRK5 regulates cytokine production in vivo by both MyD88 and TRIF dependent pathways, suggesting that GRK5 can regulate a broad range of TLRs. In the next set of studies, we used poly-microbial and mono-microbial sepsis models to further understand the role of GRK5. Indeed, our studies using polymicrobial sepsis delineates key roles for GRK5 in modulating sepsis outcome. We demonstrated that GRK5 is a critical positive regulator of inflammatory mediator production; sepsis induced thymic apoptosis and development of immune suppression. More importantly, we established that GRK5 deficiency protected mice from polymicrobial sepsis-induced mortality suggesting that GRK5 could be amenable for therapeutic targeting in sepsis. Having demonstrated the role of GRK5 in polymicrobial sepsis, we further examined the role of GRK5 in a mono-microbial acute lung infection model. Here we demonstrated that GRK5 has distinct roles in regulating progression of inflammation depending on the dose of bacteria. Our study revealed GRK5 as a crucial regulator of neutrophil chemotaxis early during infection likely via modulation of CXCL1/KC levels. In addition, we further show that GRK5 modulates bacterial burden in lungs depending on the initial dose of E. coli infection. And the regulation of bacterial burden was further dependent on the in vivo neutrophil activation status. Overall, our studies have uncovered novel roles of GRK5 during acute inflammatory disease processes and further work in discerning the involved molecular mechanisms will likely lead to therapeutic strategies to target GRK5 during sepsis-induced inflammatory conditions.
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