PROJECT 1 - Host Neuraminidases in Hemostasis and Sepsis

项目 1 - 宿主神经氨酸酶在止血和脓毒症中的作用

• 批准号: 10171428
• 负责人: JAMEY MARTH
• 金额: $ 54.93万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10171428
• 关键词: Address; Age; Aging; Alkaline Phosphatase; Anti-Inflammatory Agents; Asialoglycoprotein Receptor; Asialoglycoproteins; Biochemical; Blood; Blood Chemical Analysis; Blood Circulation; Blood Coagulation Disorders; Blood Coagulation Factor; Blood Platelets; Blood Proteins; Blood Vessels; Blood specimen; Cessation of life; Clinical; Coagulation Process; Collaborations; Data; Development; Diagnosis; Diagnostic; Disease; Disease Outcome; Enzymes; Exoglycosidases; Failure; Functional disorder; Future; Galactose; Galactosidase; Genetic; Glycoproteins; Glycoside Hydrolases; Glycosides; Half-Life; Health Care Costs; Hematology; Hemostatic function; Hepatocyte; Homeostasis; Human; Immune response; Impaired cognition; Infection; Inflammation; Investigation; Kinetics; Kupffer Cells; Laboratories; Lectin; Lectin Receptors; Ligands; Link; Location; Malignant Neoplasms; Measurement; Measures; Medical Records; Membrane Glycoproteins; Metabolic Clearance Rate; Molecular; Mus; Neuraminidase; Organ failure; Outcome; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Phenotype; Plasma; Process; Production; Prognostic Marker; Protein Glycosylation; Proteins; Proteome; Proteomics; Regulation; Research; Role; Sampling; Sepsis; Severity of illness; Sialic Acids; Signal Transduction; Specificity; Stratification; Survivors; Syndrome; Therapeutic; Thrombosis; Toxin; Urine; Vascular System; aged; base; comparative; design; healthy volunteer; human data; human mortality; insight; intravital microscopy; macrophage; mortality; mouse model; pathogen; pathogenic bacteria; patient health information; platelet homeostasis; prognostic; programs; proteostasis; rate of change; receptor; senescence; septic patients; sialylation; therapeutically effective; volunteer

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.

总结 凝血障碍和炎症是脓毒症中器官衰竭和患者死亡的主要原因。 在全世界人类死亡的前五大原因中，现在每年诊断的脓毒症病例数 超过了癌症。在幸存者中，许多人终身虚弱，认知能力下降， 广泛的血管损伤的宿主反应。几十年的失败，在发展有效的 脓毒症的治疗反映在持续的高患者死亡率上， 每年花费的医疗费用为美元。很明显，一个更大的机械 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解决了这一需要， 衰老和清除，参与调节凝血病的不同途径， 脓毒症中的炎症我们已经将新生血液的逐步翻译后重塑与 糖蛋白通过多种糖苷酶增加循环中的蛋白质年龄，并形成配体， 内吞凝集素受体。这个过程通常决定了多种血液的半衰期和功能 件.在败血症和不同的血液成分之间，这种重塑的速率改变， 病原体的身份重塑速率的增加迅速改变了关键蛋白的丰度和功能， 糖蛋白，包括抗炎酶、凝血因子和血小板。我们的研究结果是 这与脓毒症不是单一疾病机制的假设一致， 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具有重要意义。 接近。本项目的目标包括这一观点和方案的中心假设： 蛋白质糖基化和糖蛋白重塑改变脓毒症的凝血障碍和炎症。研究 本文所提出的方法包括鉴定和表征植物中的糖苷酶和凝集素受体。 血液和血管系统促进血液成分调节和凝血病机制 以及败血症中的炎症由宿主Neu 1和Neu 3神经氨酸酶去唾液酸化的血糖蛋白将被 鉴定和表征了包括靶向增加脓毒症中的内吞清除的那些。相关 血小板老化和清除的过程及其在脓毒症中的增加将被进一步研究。最近的调查结果 证明了肝细胞的Ashwell-Morell受体和 枯否细胞的巨噬细胞半乳糖凝集素。该项目还将继续收购和分析医疗 由人类脓毒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 产生机理、预后和治疗见解的联系。这些酶和受体一起 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。