Carbohydrate-Mediated Platelet Clearance

项目摘要 人体每天产生和移除1011个血小板，以维持正常的稳态血小板计数。 在破坏血小板的条件下，可以大大提高产量。我们提供了第一个证据 血小板的存活与表面多聚糖密切相关，并已表明受损的血小板 SIAα2-3Galβ1-4GlcNAc结构在肝脏中被枯否细胞和肝细胞移除。我们的数据也 结果表明，所需的血小板，即携带末端Galβ1-4GlcNAc(LacNAc)的血小板的结合 结构，到肝细胞特异性的Ashwell-Morell受体(AMR)增加血小板生成素(TPO) 在肝细胞中通过JAK2-STAT3信号产生。因此，数据表明，需要分析的血小板功能 作为骨髓(BM)和肝细胞之间的直接通信者。在这里，我们继续调查 血小板-肝细胞-骨髓通讯机制及全身信号改变的假说 缺乏AMR调节的BM动态平衡将被固化。我们将识别新的系统性因素，并 破译这些因素调节骨髓造血生态位的机制。我们目前的数据 暗示了血小板作为骨髓血管和间充质细胞的调节因子的新作用，从而影响 通过肝细胞分泌因子NRG4，特异性的ErbB4配体进行造血。最新基因组范围 关联研究(Gwas)证实了我们的初步数据：中国的单核苷酸多态性(SNPs) NRG4和NRG3基因与外周红细胞(RBC)和血小板的变化有关 数一数。我们建议研究骨髓血管、血管周围和间充质祖细胞群体和 HSC在缺乏AMR介导的血小板清除的情况下发挥作用。血小板表面糖蛋白的测量将在 NRG3/4基因SNP携带者的血小板和血浆；并确定其分子机制 在缺乏肝脏AMR介导的血小板清除的情况下，NRG4和ErbB4通过什么来调节HSC的生态位 (目标2)。

Project Summary The human body produces and removes 1011 platelets daily to maintain a normal steady-state platelet count. Production can be greatly increased under conditions of platelet destruction. We provided the first evidence that survival of platelets is intimately tied to surface glycans, and have shown that platelets with impaired Siaα2-3Galβ1-4GlcNAc structures are removed in the liver by Kupffer cells and hepatocytes. Our data also showed that binding of desialylated platelets, i.e. platelets bearing terminal Galβ1-4GlcNAc (LacNAc) structures, to the hepatocyte-specific Ashwell-Morell Receptor (AMR) increases thrombopoietin (TPO) production via JAK2-STAT3 signaling in hepatocytes. Thus the data suggest that desialylated platelet function as direct communicators between the bone marrow (BM) and hepatocytes. Here, we continue to investigate the platelet-hepatocyte-BM communication mechanism and the hypothesis that systemic signals altered in the absence of AMR regulate BM homeostasis will be solidified. We will identify novel systemic factors and decipher the mechanisms by which these factors regulate the BM hematopoietic niche. Our current data implicates a novel role of platelets as a regulator of BM vascular and mesenchymal cells, thereby affecting hematopoiesis via hepatocyte-secreted factor NRG4, the specific ErbB4 ligand. Recent genome wide association studies (GWAS) give credence to our preliminary data: Single-nucleotide polymorphisms (SNPs) in NRG4 and NRG3 genes have been associated with changes in peripheral red blood cell (RBC) and platelet count. We propose to investigate BM vascular, perivascular and mesenchymal progenitor cell populations and HSC function in the absence of AMR-mediated platelet clearance. Platelet surface glycans will be measured in platelets and plasma from individuals with SNP in NRG3/4 (Aim 1); and determine the molecular mechanisms by which NRG4 and ErbB4 regulate the HSC niche in the absence of hepatic AMR-mediated platelet clearance (Aim 2).