PROJECT 1 - Host Neuraminidases in Hemostasis and Sepsis

摘要 凝血功能障碍和炎症是脓毒症患者器官衰竭和死亡的主要原因。 在全球人类死亡的前五大原因中，现在每年诊断的脓毒症病例数量 超过了癌症。在幸存者中，许多人终身衰弱，认知能力下降 广泛的血管损伤对宿主的反应。几十年来有效发展的失败 脓毒症的治疗方法反映在患者死亡率持续居高不下，而数十亿 每年都要花费数美元的医疗费用。很明显，一个更大的机械论 需要了解这种致命综合征的分子病理生理学。这个项目 通过最近发现的糖蛋白重塑机制的拟议研究来满足这一需求， 衰老和清除，参与不同的途径调节凝血障碍和 脓毒症中的炎症。我们已经将新生血液的翻译后逐步重塑联系起来 糖蛋白通过多种糖苷酶增加蛋白质在循环中的年龄和形成配体 胞内凝集素受体。这一过程通常决定了多种血液的半衰期和功能 组件。这种重塑的比率在脓毒症和不同的血液成分之间经常联系在一起。 病原体的身份。改造率的提高迅速改变了钥匙的丰富性和功能 糖蛋白包括抗炎酶、凝血因子和血小板。我们的发现是 与败血症不是一种单一的疾病机制的假设一致，并可能被进一步理解 并通过分析离散病原体背景下宿主糖蛋白重塑的变化进行分层 身份和相关毒素。这可能对设计未来的治疗方法有重要的启示。 接近了。该项目的目标围绕着这一观点和该计划的中心假设： 蛋白糖基化和糖蛋白重塑改变了脓毒症的凝血障碍和炎症。研究 本文包括糖苷酶和凝集素受体的鉴定和特性。 血液和血管系统对血液成分的调节和凝血障碍的机制 脓毒症的炎症。被宿主Neu1和Neu3神经氨酸酶分析的血糖蛋白将被 确定和表征，包括针对脓毒症时增加内吞清除量的那些。相关的 脓毒症时血小板老化和清除的过程及其增加将被进一步研究。最新发现 展示了肝细胞的Ashwell-Morell受体和 枯否细胞巨噬细胞半乳糖凝集素。该项目还将继续获取和分析医疗 由人类败血症患者和志愿者提供的记录和血液样本，以实现进一步的翻译 链接产生机制，预测和治疗的见解。这些酶和受体结合在一起 在脓毒症的分层和发病机制中，有助于不同和重叠的分子途径。

SUMMARY Coagulopathy and inflammation are the primary contributors to organ failure and patient death in sepsis. Among the top five causes of human mortality worldwide, the number of sepsis cases diagnosed annually now exceeds that of cancer. Among survivors, many suffer lifelong debilitation with cognitive decline from the extensive vascular damage of the host response. Decades of failure in the development of effective therapeutics for sepsis are reflected by the continuing high rate of patient mortality while many billions of dollars of healthcare costs are expended annually. It has become evident that a greater mechanistic understanding is needed regarding the molecular pathophysiology of this deadly syndrome. This project addresses this need with proposed research of a recently discovered mechanism of glycoprotein remodeling, senescence, and clearance that participates in disparate pathways modulating the coagulopathy and inflammation in sepsis. We have linked the step-wise post-translational remodeling of nascent blood glycoproteins by multiple glycosidases to increased protein age in circulation and to the formation of ligands for endocytic lectin receptors. This process normally determines the half-lives and functions of multiple blood components. Rates of this remodeling are altered in sepsis and among different blood components often linked to pathogen identity. Increased rates of remodeling rapidly change the abundance and functions of key glycoproteins including anti-inflammatory enzymes, coagulation factors, and platelets. Our findings are consistent with the hypothesis that sepsis is not a singular disease mechanism and may be further understood and stratified by analyzing alterations in host glycoprotein remodeling in the context of discrete pathogen identities and associated toxins. This may have important implications for designing future therapeutic approaches. The aims of this project encompass this perspective and the central hypothesis of the program: Protein glycosylation and glycoprotein remodeling alter the coagulopathy and inflammation of sepsis. Research proposed herein includes the identification and characterization of glycosidases and lectin receptors in the blood and vascular systems contributing to blood component modulation and mechanisms of coagulopathy and inflammation in sepsis. Blood glycoproteins desialylated by host Neu1 and Neu3 neuraminidases will be identified and characterized including those targeted for increased endocytic clearance in sepsis. The related process of platelet aging and clearance and its increase in sepsis will be further investigated. Recent findings demonstrate a mysterious collaborative interaction between the Ashwell-Morell receptor of hepatocytes and the macrophage galactose lectin of Kupffer cells. This project will also continue to acquire and analyze medical records and blood samples provided by human sepsis patients and volunteers to achieve further translational links yielding mechanistic, prognostic, and therapeutic insights. These enzymes and receptors together contribute to distinct and overlapping molecular pathways in the stratification and pathogenesis of sepsis.