The long-term objective is to determine the role of leukocytes in human lung disease. The proposed studies may lead to therapies to modify the immune response. The proposed work will be an investigation of an adhesion molecule that is found on human lymphocytes and eosinophils. This adhesion molecule, integrin alpha4beta7, is one of the integrin family of cell surface proteins. Integrins mediate adhesion of cells to extracellular matrix proteins and to vascular endothelial cells. Integrins are necessary for leukocyte migration into tissues. Integrin alpha4beta7 was identified in human lung airway leukocytes. Integrin alpha4beta7 mediates cell adhesion to mucosal addressin, a protein located on endothelium in mucosal lymphoid tissue. Leukocytes that adhere to mucosal addressin then migrate into these tissues. Thus, alpha4beta7 and mucosal addressin interact and direct leukocytes into specific tissues.
The aims of this work are to determine the amino acid residues of the cytoplasmic domain of the beta7 integrin subunit that are involved in signal transduction by alpha4beta7, and regulation of cell adhesion mediated by alpha4beta7. The beta7 subunit cDNA will be mutated to alter the structure and amino acid sequence of the cytoplasmic domain. The mutated beta7 proteins will be expressed in cultured cell lines. In vitro adhesion assays will demonstrate the effects of the mutations on cell adhesion and on signal transduction by alpha4beta7. Experiments will then analyze the function of alpha4beta7 in human T cells. The results of these experiments could suggest therapies for immune and inflammatory diseases of the lung.
| Tidswell, M; Pachynski, R; Wu, S W et al. (1997) Structure-function analysis of the integrin beta 7 subunit: identification of domains involved in adhesion to MAdCAM-1. J Immunol 159:1497-505 |
| Abitorabi, M A; Pachynski, R K; Ferrando, R E et al. (1997) Presentation of integrins on leukocyte microvilli: a role for the extracellular domain in determining membrane localization. J Cell Biol 139:563-71 |
