The purpose of the project is to molecularly clone and characterize novel chemokine receptors in activated lymphocytes. Chemokines are members of a family of more than thirty human cytokines whose best described activities are as chemotactic factors for leukocytes. Chemokines act through cell-surface proteins, ie. receptors, that are members of the G protein coupled receptor superfamily. Chemokines and their receptors are increasingly recognized as important in the trafficking of lymphocytes in immune and inflammatory responses as well as other aspects of lymphocyte physiology. Because lymphocytes are important in responses to infectious agents as well as in autoimmune diseases, inflammatory disorders, and transplant rejection, secreted factors and receptors that effect lymphocyte recruitment to tissue are potentialtargets for therapeutic interventions. Characterization of chemokine receptors on lymphocytes is of added medical relevance given the recent discoveries that chemokine receptors function as obligate co-receptors for HIV-1 entry, so that understanding these receptors may lead to novel therapies for preventing and treating HIV infection. The work involves molecular cloning of candidate receptors from activated human T cells and analysis of receptor function in vitro and in animals. Cloning of new receptors is based on the structural similarities among known members of the chemokine receptor family using standard methodology of molecular biology. Functional studies begin with developing the appropriate tools such as cell lines expressing the receptor of interest in the absence of other related receptors as well as anti-receptor antibodies. Subsequent functional analysis of receptors involves testing potential ligands for signaling and binding and testing for activity as co-receptors for the human and simian immunodeficiency viruses. Additional in vitro studies of receptor expression and signaling on human and mouse cells will direct subsequent in vivo experiments in mice. These latter experiments will include developing mice with targeted disruptions/deletions in the receptor genes. To date, two novel receptors have been discovered in the course of this project- STRL22 and STRL33- and an additional orphan receptor, GPR-9-6, has been characterized. STRL22 is a receptor for the chemokine MIP-3alpha, and STRL22 has been renamed CCR6. The ligand for STRL33 is unknown. STRL33, however, can function as a co-receptor for some strains of HIV-1, HIV-2, and SIV. GPR-9-6 exists in two forms that can function as receptors for the chemokine TECK/CCL25, and these two forms will be called CCR9A and CCR9B. - Chemokines, lymphocytes, receptors, HIV, SIV
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