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 neutrophils, monocytes, macrophages, and lymphocytes in vitro. It seems reasonable, although not yet thoroughly tested in vivo, that this mechanism of activation contributes significantly to host defense, as well as to the many pathologic states characterized by excessive idiopathic inflammation. The rationale for this project is to understand the molecular mechanisms involved in activation of leukocytes by extracellular matrix. Several years ago, we found that in addition to integrins, a non-integrin protein of the phagocyte plasma membrane was required for extracellular matrix-induced activation. We termed this IgV superfamily member with multiple transmembrane domains Integrin- Associated Protein (IAP) because of its physical and functional association with phagocyte integrins. Over the past 4 years, we have cloned human and murine IAP cDNAs, characterized the IAP gene, discovered the existence and determined the expression of IAP isoforms in vivo, found a peptide ligand for IAP, discovered additional functions for IAP, set up appropriate models for studying IAP signal transduction, and made a mouse which does not express IAP because of a targeted gene disruption. We propose to continue this work in the next grant period by extending these in vitro and in vivo studies to understand the molecular basis for the role of IAP in leukocyte activation by extracellular matrix. Specifically, we will determine the structural requirements in the IAP Ig domain for interaction with its known ligands, (Beta3- integrin and thrombospondin- 1; we will determine which IAP domains are required for signal transduction; and we will assess the function of leukocytes from the IAP -/- mouse in vivo and in vitro. These studies will contribute greatly to understanding and ultimately control of the inflammatory response.
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