With the proposed Mentored Clinical Scientist Development Award, the candidate will build upon his prior experiences in studying RNA biochemistry to enhance his skills in Molecular Biology, Cell Biology, and Immunology. The laboratory of Dr. Andrew D. Luster at the Massachusetts General Hospital will provide a rich intellectual environment to foster the candidate's scientific development toward his goal of independent investigation. The proposed study will provide the candidate with the opportunity to study chemokine mediated signaling pathways that control the movement of leukocytes. Chemokines interact with specific G protein coupled receptors to initiate a cascade of events resulting in the migration of target cells as well as to induce other responses essential for immune function. The signal transduction pathways activated by specific chemokine receptors to induce chemotaxis are not well defined. Dr. Luster has a long-standing interest in interferon-inducible protein of 10 kDa (IP-10), a molecule critical for the directed migration of activated T lymphocytes. The proposed research focuses on the role of the IP10 receptor, CXCR3, in mediating the migration of activated T lymphocytes. Three ligands bind CXCR3: IP-10, Mig, and I-TAC. CXCR3 and its ligands play integral roles in the accumulation of T lymphocytes in autoimmune inflammation, atherosclerotic disease, viral, fungal, and parasitic infections, and delayed type hypersensitivity responses. Despite binding to the same receptor, each of these ligands causes distinct effects in cells expressing CXCR3. For example, we have found that while I-TAC binding effectively results in CXCR3 internalization, binding of neither IP-10 nor Mig effectively causes internalization. To this end, this application has four specific aims: (1) To determine the external domains of CXCR3 involved in the differential binding and signaling of IP-I0, MIG, and I-TAC. (2) To determine the internal domains of CXCR3 responsible for transducing the signals necessary for calcium and inositol triphosphate mobilization, receptor internalization, chemotaxis, and integrin activation. (3) To determine the role of internalization and desensitization of CXCR3 in T cell trafficking in vivo. (4) To determine the epitopes of IP-I0 responsible for activating the specific signaling pathways of CXCR3.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Clinical Investigator Award (CIA) (K08)
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Allergy & Clinical Immunology-1 (AITC)
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Prograis, Lawrence J
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Massachusetts General Hospital
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Colvin, Richard A; Campanella, Gabriele S V; Manice, Lindsay A et al. (2006) CXCR3 requires tyrosine sulfation for ligand binding and a second extracellular loop arginine residue for ligand-induced chemotaxis. Mol Cell Biol 26:5838-49
Colvin, Richard A; Campanella, Gabriele S V; Sun, Jieti et al. (2004) Intracellular domains of CXCR3 that mediate CXCL9, CXCL10, and CXCL11 function. J Biol Chem 279:30219-27
Swaminathan, G Jawahar; Holloway, Daniel E; Colvin, Richard A et al. (2003) Crystal structures of oligomeric forms of the IP-10/CXCL10 chemokine. Structure 11:521-32