CXC chemokine receptor internalization and recycling are key events in the modulation of biological responses to chemokines and these regulatory events vary among chemokine receptors and among cell types. We hypothesize that receptor internalization is needed for the intracellular trafficking of activated AKT and PAK to the leading edge of the cell during chemotaxis and that by altering CXCR2 receptor desensitization, sequestration, or recycling, we can alter cutaneous wound healing, inflammatory response, and maintenance of epithelial homeostasis in vitro and in vivo. We have identified a number of proteins, which bind to the carboxyl-terminal domain of CXCR2 and we further hypothesize that these proteins are involved in the regulation of CXCR2 signal transduction, desensitization, internalization, and/or recycling. To test these hypotheses we propose the following four specific aims.
Under Aim1 we will test murine models for the biological impact of expression of mutants of CXCR2 with altered desensitization, internalization, and recycling properties. Wound healing properties of transgenic mice and """"""""knock in"""""""" mice, which express a desensitization defective form of CXCR2 will be studied in response to excision wounding.
Aim II is to determine the effects of the loss of CXCR2 internalization on ligand mediated signal transduction as a result from loss of functional interaction with specific adaptor proteins or chaperonines.
Aim III will determine whether alteration of ligand mediated internalization of CXCR2 affects the trafficking of AKT to the leading edge of the cell and the trafficking of activated PAK to the uropod during chemokine mediated chemotaxis.
Under Aim I V we will characterize the pathway involved in the intracellular trafficking of CXCR2. We will utilize the colocalization of specific Rab GTPases with CXCR2 to follow the intenalization/endosomal sorting and recycling of CXCR2 to the plasma membrane. These studies will provide new understanding of how these chemokine receptors are regulated and the signals generated to enable chemotaxis. The information obtained will provide important insight for better design of therapeutic strategies for treatment of chronic inflammatory diseases, chronic wounds, and cancers
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