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， 肺泡毛细血管渗漏和在显著环境损伤后发生的微血栓形成（1-3）。的 在美国，估计每年有190，000人患有该综合征，估计死亡率为30 40%（4）。最常见的急性呼吸窘迫综合征的诱因是败血症， 在感染环境中的炎症（5）。尽管死亡率高，但没有有效的药理学 治疗ARDS。因此，有显着的兴趣，确定新的途径参与ARDS 发病机制ABO基因编码一个催化特异性抗原的糖基转移酶家族 各种细胞表面的修饰并表征ABO血型。ABO血型是已知的 影响某些传染病和血管疾病风险以及与 ARDS（13-21），导致ABO血型与ARDS风险相关的假设。 拟议项目的主要目标是：1）确定ABO血型与 严重脓毒症和脓毒性休克患者的ARDS风险; 2）确定以下因素的相对贡献： 候选血浆蛋白，以观察ABO血型和ARDS之间的关联; 3）训练候选血浆蛋白， 候选人在队列研究设计和管理，生物标志物测量和分析， 因果路径分析模型; 4）为申请人提供个性化的指导，以确保他 过渡到独立调查员的角色。 申请方将使用现有的成熟的重度脓毒症受试者队列。目前，临床数据 前瞻性地收集血浆样本，并在重症监护室就诊时抽取血浆样本， 可供研究。将从病历中提取ABO血型，并检测其与以下疾病的相关性： ARDS的发展。此外，已知与ABO血型相关的候选血浆蛋白 和ARDS将被测量和测试，以确定这些蛋白质介导的程度， ABO血型与ARDS的关系申请人将完成这些目标，同时从事 在一个严格的教学课程和一对一的指导与高级调查员的培训计划 接受过流行病学和危重病转化研究方面的培训。此外，该项目的成果 有可能发现一种与脓毒症相关的ARDS发病机制有关的新途径。见解 这项研究将指导未来的机制和治疗研究，旨在ABO糖生物学。

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.