Molecular Genetics of Integrin Collagen Receptors

整合素胶原蛋白受体的分子遗传学

• 批准号: 6828439
• 负责人: THOMAS J. KUNICKI
• 金额: $ 46.93万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6828439
• 关键词: CpG islands; DNA methylation; cell differentiation; clinical research; collagen; family genetics; gene expression; gene induction /repression; genetic promoter element; genetic susceptibility; genetic transcription; genetically modified animals; genotype; haploidy; hemorrhage; human subject; integrins; laboratory mouse; megakaryocytes; molecular genetics; patient oriented research; phlebotomy; platelets; von Willebrand' s disease

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.

描述（由申请人提供）：整合素α -1基因（ITGA1）和α -2基因（ITGA2）各自编码一个指导胶原特异性的亚基。这些基因彼此非常接近，在人类第5染色体和小鼠第13染色体上形成一个整合素基因位点。我们提出，这些基因的转录调控是通过在人类和小鼠中对该位点的结构和/或分子影响来协调的。另一个重要的血小板胶原受体GPVI在巨核细胞成熟过程中受到差异调节。我们提出在巨核细胞中，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。我们的目标是表征这些基因的协调调节及其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，本项目有三个具体目标：1)表征人类和小鼠巨核细胞中ITGA2表达的单倍型特异性控制；2)表征两种动物巨核细胞中ITGA1表达的谱系特异性抑制；3)探讨ITGA2单倍型遗传与血管性血友病（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粘附受体表达遗传差异的分子基础，并增加我们对巨核细胞成熟和分化过程中这些粘附受体基因调控表达的机制的理解。从临床角度来看，这些研究还将揭示这些基因差异对血管性血友病等出血性疾病不良事件风险的影响。