Biology of the Human Platelet Fc(gamma) Receptor

人血小板Fc γ受体在以血小板减少症、血栓形成或血管炎为特征的几种血液学病症中起重要作用。在过去的15年中，对血小板Fc γ受体的认识不断增长。本研究组和其他研究人员已经对其遗传学、调控表达和结构/功能关系以及其在免疫病理学中的作用进行了研究。我们项目的长期目标是更全面地破译血小板Fc γ的分子机制，即细胞内Fc γ受体生物学。 为了给免疫性血小板疾病提供更安全、更合理的治疗，另外，对血小板Fc γ受体的遗传学、表达调控和信号通路的研究与本项目的其他项目保持协同作用。该提案的具体目标是：1。检查血小板Fc γ RIIA与巨噬细胞Fc γ RIIA在体内免疫清除中的作用。我们的假设是Fc γ RllA的表达在体内调节免疫复合物的命运中起主要作用，并且ptatelet的废除可能导致免疫复合物的死亡。 尽管持续的巨噬细胞表达，但Fc γ受体将导致免疫复合物的异常清除。血小板特异性Fc γ RIIA转基因小鼠以及巨噬细胞特异性Fc γ RIIA转基因小鼠将通过使用具有附加至Fc γ RIIA基因编码区的细胞特异性启动子序列的DNA构建体来产生。2.检测血小板Fc γ受体表达的调节。血小板Fc γ RIIA的水平与其在健康和疾病中的功能相关。我们的假设是Fc γ R11A基因调控序列的遗传变异，例如我们最近鉴定的启动子单核苷酸多态性（SNP），决定Fc γ R11A表达水平的差异。SNP对Fc γ RIIA表达的作用机制将在体外用由巨核细胞中Fc γ RIIA基因的遗传同种型驱动的转染报告基因进行研究，并在体内用Fc γ RIIA变体产生的新转基因小鼠系中进行研究。3.研究Cbl在免疫清除、内吞和血小板活化中的作用。我们已经确定了Cbl在体外Fc γ RIIA介导的内吞作用中的重要性，并将Cbl敲除小鼠与我们的Fc γ RIIA转基因小鼠杂交。我们的假设是，Cbl是重要的Fc γ RIIA内吞作用在河流和Fc γ RIIA亚细胞定位。血小板Fc γ受体生物学的持续进展 应该允许更好的诊断和治疗患者的免疫ptatelet疾病。

The human platelet Fcgamma receptor plays an important role in several hematologic disorders characterized by thrombocytopenia, thrombosis or vasculitis. Over the past 15 years, knowledge of the platelet Fcgamma receptor has grown. Aspects of its genetics, regulated expression and structure/function relationships, as well as its function in rive in immune pathology, have been studied by our group and others. The long term goai of our project is to more fully decipher the molecular mechanisms underlying piatelet Fcgamma, receptor biology in order to provide safer and more rational therapy for the immune platelet disorders, in addition, studies of the genetics, regulated expression, and signaling pathways of the platelet Fcgamma receptor remain synergistic with the other projects of our Program Project. The Specific Aims of this proposal are: 1. To examine the role of platelet FcgammaRIIA vs macrophage FcgammaRIIA in immune clearance in vivo. Our hypothesis is that the expression of FcgammaRllA ptays a major rote in regulating the fate of immune complexes in vivo, and that abrogation of ptatelet Fcgamma receptors, despite continued macrophage expression, will lead to aberrant clearance of immune complexes. Platetet-specific FcgammaRIIA transgenic mice as well as macrophage-specific FcgammaRIIA transgenic mice will be generated by use of DNA constructs with celt-specific promoter sequences appended to the coding region of the FcgammaRIIA gene. 2. To examine the regulation of expression of the platelet Fcgamma receptor. The level of platetet FcgammaRIIA correlates with its function in health and disease. Our hypothesis is that genetic variation in FcgammaRllA gene regulatory sequences, such as the promoter single nucleotide polymorphisms (SNPs) we recently identified, determine differences in the level of FcgammaRIlA expression. The mechanism of the SNP effects on FcgammaRllA expression will be studied in vitro with transfected reporter genes driven by genetic isoforms of the FcgammaRllA gene in megakaryocytic ceils, and in vivo in new transgenic mouse lines created with FcgammaRlIA variants. 3. To examine the role of Cbl in immune clearance, endocytosis and platelet activation. We have established the importance of Cbl in FcgammaRIIA mediated endocytosis in vitro and have crossbred Cbl knockout mice to our FcgammaRIIA transgenic mice. Our hypothesis is that Cbl is important for both FcgammaRIIA endocytosis in rive and FcgammaRIIA subcellutar localization. Continued progress in platelet Fcgamma, receptor biology should permit better diagnosis and therapy for patients with immune ptatelet disorders.