Chemotactic cytokines, known as chemokines, modulate the inflammatory response, wound healing, tumorigenesis, angiogenesis, and pathogen entry into cells. Chemokine subfamilies are denoted based upon the structural presentation of the first two cysteine residues as CXC or CC. Chemokines exert their effects by binding to seven-transmembrane-G protein-coupled receptors and transducing intracellular signals which include activation of serine and tyrosine kinases and mobilization of calcium. Chemokine receptors (CXCR or CCR, depending upon the subfamily of chemokines the receptors bind) are present on leukocytes, endothelial cells, epithelial cells, melanocytes, macrophages, and dendritic cells. Disregulation of chemokine/ chemokine receptor expression is associated with a number of disorders: chronic inflammatory diseases such as rheumatoid arthritis, ARDS, and psoriasis, sepsis, angiogenesis associated with tumorigenesis, squamous cell carcinoma and melanoma. So that they might better understand the mechanism by which CXC chemokines regulate the immune response, wound healing and cell growth, they have partially characterized signal transduction through the CXCR2 receptor for CXC chemokines and the events involved in desensitization and sequestration of CXCR2. To further explore the hypothesis that CXC chemokines acting through CXCR2 regulate important events of cell migration, cell growth, and wound healing, they propose to more completely characterize the signal transduction pathway through CXCR2 and explore in vitro and in vivo models involving expression of gain and loss of function CXCR2 receptors in keratinocytes. There are three aims: 1) to develop in vitro and in vivo models to examine the biological consequence of gain or loss of function of CXCR2 receptors in the epidermis during wound healing; 2) to characterize the events which occur in response to ligand binding to CXCR2 which facilitate homologous/heterologous cross desensitization and CXCR2 sequestration; and 3) to characterize the role of tyrosine phosphorylation of pyk2, src, and p130CAS in the cell motility responses mediated through CXCR2. Characterization of the events of signaling and receptor sequestration and desensitization will facilitate rationale drug design for disorders where sustained sensitivity to chemokines is essential for therapeutic efficacy.
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