Molecular Genetics of Integrin Collagen Receptors

描述(由申请人提供)：整合素α-1基因(ITGA1)和α-2基因(ITGA2)各自编码一个亚基，指导胶原蛋白的特异性。这些基因紧密相连，在人类5号染色体和小鼠13号染色体上形成一个整合素基因座。我们认为，这些基因的转录调控是通过结构和/或分子上对该基因座的影响来协调的，在人类和小鼠中都是如此。另一种重要的血小板胶原受体GPVI在巨核细胞成熟过程中受到不同程度的调节。我们认为，在巨核细胞中，ITGA1的下调、GP6的上调和这些启动子区域的CpG甲基化/去甲基化之间存在重要的时间关系。我们的目标是描述这些基因的协调调节以及它们在巨核细胞分化和血小板功能中的作用。为了解决这些问题，该项目有三个具体的目标：1)表征ITGA2在人和小鼠巨核细胞中表达的单倍型特异性控制；2)表征在这两个物种的巨核细胞中ITGA1表达的谱系特异性抑制；以及3)ITGA2单倍型的遗传与von Willebrand病(VWD)症状性出血风险的相关性。这些研究的成功完成将有助于深入了解黏附受体表达遗传差异的分子基础，并加深我们对这些黏附受体基因在巨核细胞成熟和分化过程中表达调控机制的理解。从临床角度来看，这些研究还将揭示这些基因差异对Von Willebrand病等出血性疾病不良事件风险的影响。

DESCRIPTION (provided by applicant): 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.