The overall hypothesis of this application is that integrins are critical for development of inflammatory and immune responses because of their involvement in leukocyte homing to sites of injury, transendothelial migration, and chemotaxis through basement membrane and extracellular matrix. Integrins may also be important as transmembrane signalling molecules in the generation of inflammation and immunity. Because the function of integrins of the beta2 family known as LeuCAMs have been studied in some detail, the aim of this application is to examine the structure and function of leukocyte integrins other than LeuCAMs, which are also critical in the normal host response to infectious and inflammatory stimuli. For example, beta1 integrins, such as VLA-3, VLA-4 and VLA-5 play an important role in modulation of lymphocyte proliferation. Our preliminary data suggest that there are additional functionally important integrins expressed on immune cells. At least one of these integrins, Leukocyte Response Integrin (LRI), remains uncharacterized at a molecular level. A non-integrin membrane protein, Integrin Associated Protein (IAP), has been associated with integrin signal transduction. Because of the complexity of integrin expression on a given cell type and the undoubted overlap in function of various integrins, understanding of structure, peptide specificity, and expression of any integrin is an important and requisite component of understanding its function. Therefore, this application integrates structural and functional studies in each specific aim. The first specific aim of this proposal is to characterize a novel integrin beta (beta/n) on leukocytes. This will include determination of the primary structure of beta/n; characterization of the beta/n chains on lymphocytes, monocytes, and PMN; determination of whether beta/n is the LRI beta chain; a description of the beta/n-associated alpha chain(s); and determination of the functional role of beta/n using specific monoclonal antibodies as well as cDNA transfection studies. The second specific aim of the proposal is to examine the function of IAP on lymphocytes. Specific signal transduction systems in which this molecule may play a role, including B lymphocyte proliferation, T lymphocyte proliferation in response to extracellular matrix, homotypic lymphocyte aggregation, and lymphocyte chemotaxis will be investigated. A determination of IAP- associated integrins will also be made. These studies will further understanding of leukocyte responses to extracellular matrix during inflammation, infection, and tissue injury. This understanding can, in turn, be used in the development of novel therapies for diseases characterized by exuberant and harmful inflammatory responses.
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