The integrin alpha-1 gene (ITGA1) and alpha-2 gene (ITGA2) each encode a subunit that directs specificity for collagens. These genes reside very close to one another forming an integrin gene locus on human chromosome 5 and murine chromosome 13. We propose that the transcriptional regulation of these genes is coordinated by structural and/or molecular influences upon this locus both in humans and in mice. Another important platelet collagen receptor, GPVI, is differentially regulated during megakaryocyte maturation. We propose that there is an important temporal relationship between the downregulation of ITGA1, the upregulation of GP6 and CpG methylation/demethylation of these promoter regions in megakaryocytes. Our goal is to characterize the coordinated regulation of these genes and their role in megakaryocyte differentiation and platelet function. To address these questions, this project has three specific aims: 1) To characterize the haplotype-specific control of ITGA2 expression in human and murine megakaryocytes; 2) To characterize the lineage-specific suppression of ITGA1 expression in megakaryocytes of both species; and 3) To correlate inheritance of ITGA2 haplotypes with risk for symptomatic bleeding in von Willebrand Disease (VWD). The successful completion of these studies will provide insight into the molecular basis for inherited differences in adhesion receptor expression and increase our understanding of the mechanisms involved in regulated expression of these adhesion receptor genes during megakaryocyte maturation and differentiation. From a clinical standpoint, these studies will also reveal the impact of these gene differences on risk for adverse events in bleeding disorders such as Von Willebrand Disease.
