ABO Glycosyltransferases in Sepsis Associated Acute Respiratory Distress Syndrome

项目摘要 急性呼吸窘迫综合征(ARDS)是一种炎症、内皮功能障碍、 肺泡毛细血管渗漏，以及在重大环境伤害后发生的微血栓形成(1-3)。这个 据估计，美国每年有19万人患有这种综合症，估计死亡人数为30 至40%(4)。ARDS最常见的诱因是败血症，这是一种全身调节失调的综合征 感染环境中的炎症(5)。尽管死亡率很高，但目前还没有有效的药物 ARDS的治疗。因此，确定与ARDS有关的新途径具有重要意义 发病机制。ABO基因编码一系列糖基转移酶，催化特定的抗原。 不同细胞表面的修饰和ABO血型的特征。ABO血型是已知的 影响某些传染病和血管疾病的风险以及与以下疾病有关的血浆糖蛋白水平 ARDS(13-21)，导致假设ABO血型与ARDS的风险有关。 拟议项目的广泛目标是：1)确定ABO血型和 严重脓毒症和感染性休克患者的不良反应风险；2)确定 候选血浆蛋白以观察ABO血型与ARDS之间的关系；3)培训 队列研究设计和管理、生物标记物测量和分析以及统计学专业候选人 因果路径分析模型；4)为申请者提供个性化指导，以确保其 过渡到独立调查员的角色。 申请者将使用现有的发育良好的严重脓毒症受试者队列。目前，临床数据 是前瞻性采集的，血浆样本在提交给重症监护病房时抽取，并 可供学习。ABO血型将从医疗记录中提取出来，并进行与 急性呼吸窘迫综合征的发展。此外，已知与ABO血型相关的候选血浆蛋白 将对ARDS进行测量和测试，以确定这些蛋白质在多大程度上介导了 ABO血型与急性呼吸窘迫综合征的关系申请者将在参与的同时完成这些目标 在讲授课程和一对一指导的严格培训计划中，有一名高级调查员 接受过危重疾病流行病学和转化性研究方面的培训。此外，该项目的成果已经 发现与脓毒症相关的ARDS发病机制有关的新途径的可能性。真知灼见 这项研究将指导未来针对ABO糖生物学的机制和治疗研究。

Project Summary The acute respiratory distress syndrome (ARDS) is a syndrome of inflammation, endothelial dysfunction, alveolar capillary leak, and microthrombosis that occurs after a significant environmental insult (1-3). The syndrome affects an estimated 190,000 people in the United States annually, with an estimated mortality of 30 to 40% (4). The most common precipitating cause of ARDS is sepsis, the syndrome of dysregulated systemic inflammation in the setting of an infection (5). Despite high mortality, there is no effective pharmacologic therapy for ARDS. Therefore, there is significant interest in identifying novel pathways involved in ARDS pathogenesis. The ABO gene encodes a family of glycosyltransferases that catalyze specific antigen modifications on various cell surfaces and characterize the ABO blood group. ABO blood type is know to influence risk of certain infectious and vascular diseases as well as plasma levels of glycoproteins implicated in ARDS (13-21), leading to the hypothesis that ABO blood type is associated with the risk of ARDS. The broad objectives of the proposed project are to: 1) determine the association of ABO blood type and ARDS risk among patients with severe sepsis and septic shock; 2) determine the relative contribution of candidate plasma proteins to observed associations between ABO blood types and ARDS; 3) train the candidate in cohort study design and management, biomarker measurement and analysis, and statistical models for causal pathway analyses; 4) provide the applicant with individualized mentoring to ensure his transition to the role of an independent investigator. The applicant will use an existing well-developed cohort of subjects with severe sepsis. Currently, clinical data is collected prospectively and plasma samples are drawn at presentation to the intensive care unit and are available for study. ABO blood type will be extracted from the medical record and tested for associations with the development of ARDS. In addition, candidate plasma proteins known to be associated with ABO blood type and ARDS will be measured and tested to determine the extent to which these proteins mediate the relationship between ABO blood type and ARDS. The applicant will complete these objectives while engaging in a rigorous training program of didactic coursework and one-on-one mentoring with a senior investigator trained in epidemiologic and translational research of critical illness. Moreover, the results of the project have the potential to identify a novel pathway implicated in the pathogenesis of sepsis associated ARDS. Insights from this study will guide future mechanistic and therapeutic research aimed at ABO glycobiology.