It is now well accepted that an important aspect of leukocyte interaction with extracellular matrix is that cell activation occurs as a result of integrin ligation by extracellular matrix proteins. There is now abundant evidence, generated from many laboratories, that extracellular matrix proteins can activate the proinflammatory functions of leukocytes in vitro and there is increasing data that this mechanism of activation contributes significantly to host defense and to pathologic states characterized by excessive idiopathic inflammation in vivo. The rationale for his project is to understand the molecular mechanisms involved in activation of leukocytes by extracellular matrix. Several years ago he found that in addition to integrins, a non-integrin protein of the phagocyte plasma membrane was required for extracellular matrix-induced activation. He called this IgV superfamily member with multiple transmembrane segments Integrin-Associated Protein (IAP) because of its physical and functional association with phagocyte integrins. Over the course of this project, Dr. Brown has cloned IAP ligands, made an IAP knockout mouse by targeted gene disruption and studied its host defense, set up appropriate models for studying IAP signal transduction, and demonstrated IAP association with heterotrimeric G proteins and with a novel family of cytoskeletal proteins that link IAP to intermediate filaments. Dr. Brown proposes to continue this work in the next project period by extending these in vitro and in vivo studies to understand the molecular basis for the role of IAP in leukocyte activation. Specifically, he proposes to determine i) how the multiple membrane-spanning domain influences IAP ligand binding and signaling; ii) the mechanism and significance of IAP interaction with intermediate filaments; and iii) how IAP regulates transendothelial leukocyte migration. These studies will contribute greatly to the understanding and ultimately the control of the inflammatory response.
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