CD11/CD18 (leukocyte adhesion molecules LFA- 1, CR3 and p150,95) is a family of three surface membrane glycoprotein heterodimers which serves crucial roles in leukocyte adhesion functions. Each of the alpha subunits (CD11) is noncovalently linked to a common beta subunit (CD18). These glycoproteins are members of a larger family of heterodimeric receptors (Integrins) mediating specific cell-cell & cell-matrix interactions, which include human platelet gplIb/IIIa and fibronectin receptors and position-specific antigens in Drosophila. CDll/CD18 complex mediates crucial white blood cell functions (e.g. chemotaxis, phagocytosis, aggregation & adhesion to and migration across endothelial cells) both in vitro and in vivo. Several disease states, congenital or acquired, are characterized by abnormal expression of these gene products. Inherited lack of surface expression of these glycoproteins predisposes to life-threatening bacterial infections in humans. Deficient expression of these adhesion molecules on the surface of cent lymphomas may contribute to their leukemic transition as well as their escape from immune surveillance. Increased surface expression of CD11/CD18 on the other hand, as seen in diabetic monocytes or granulocytes from patients during hemodialysis may contribute respectively to the vascular and hemodynamic and pulmonary complications of these diseases. In addition, certain structural and developmental features make studies of gene regulation of CD11/CD18 highly relevant. Expression of the highly homologous CD11 genes occurs in a tissue- and cell-specific manner and responds distinctly to differentiation and environmental stimuli. The nonhomologous CD18 gene is concomitantly expressed by the same stimuli that result in the unique and cell-specific expression of the homologous CD11 subunits thus providing an ideal system for studying coevolution of cis and transacting elements in structurally unrelated genes. We propose to analyze the structure and locate cis-acting genetic elements controlling tissue-specific and inducible expression of CD11b and CD18 genes. Gene structure will be elucidated by restriction mapping and DNA sequencing. Cis-acting regulatory gene elements will be identified by gene transfer and site-directed mutagenesis. Elucidation of the organization of these genes and of the mechanisms involved in their transcriptional regulation should be instrumental in understanding the pathogenesis of inherited CD11/CD18 deficiency and the molecular basis for altered cell adhesion in other common disease states. These studies would also shed fight on some of the mechanisms involved in tissue-specific and inducible expression during differentiation of distinct but functionally related genes and will lay the ground work for further studies to identify the responsible factors. The generated data should also permit comparisons of the evolution, regulation and function of the related genes in the integrin family.
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