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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IMS (01))
Program Officer
Marino, Pamela
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University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
United States
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Su, Xiao; Johansen, Mette; Looney, Mark R et al. (2008) CD47 deficiency protects mice from lipopolysaccharide-induced acute lung injury and Escherichia coli pneumonia. J Immunol 180:6947-53
Johansen, Mette L; Brown, Eric J (2007) Dual regulation of SIRPalpha phosphorylation by integrins and CD47. J Biol Chem 282:24219-30
Rebres, Robert A; Kajihara, Kimberly; Brown, Eric J (2005) Novel CD47-dependent intercellular adhesion modulates cell migration. J Cell Physiol 205:182-93
N'Diaye, Elsa-Noah; Brown, Eric J (2003) The ubiquitin-related protein PLIC-1 regulates heterotrimeric G protein function through association with Gbetagamma. J Cell Biol 163:1157-65
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Lindberg, F P; Bullard, D C; Caver, T E et al. (1996) Decreased resistance to bacterial infection and granulocyte defects in IAP-deficient mice. Science 274:795-8

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