The Role of ABO Glycosyltransferases in the Acute Respiratory Distress Syndrome

 描述（由申请方提供）：在美国，急性呼吸窘迫综合征（ARDS）每年影响约190，000人，死亡率和发病率较高;然而，ARDS的有效药物治疗很少。因此，有显着的兴趣，在确定新的ARDS危险因素，可能导致未来的治疗目标，并确定人群最有可能受益于这种疗法。ABO基因编码一个糖基转移酶家族，该家族催化细胞上的特定碳水化合物修饰并表征ABO血型。已知ABO基因变异会影响感染性和血管疾病的风险以及与ARDS有关的糖蛋白的血浆水平，包括血管性血友病因子（vWF）和可溶性细胞间粘附分子-1（sICAM-1）。我们最近报道了A型血与ARDS风险增加之间的新关联，与血管疾病的先前发现一致。本研究的主要目的是：1）确定ABO基因变异在改变创伤和严重脓毒症患者群中的ARDS风险中的作用; 2）确定相关基因FUT 2和FUT 3的功能变异在ARDS中的作用，以及FUT 2决定的“分泌”状态在改变ABO和ARDS之间的关联中的作用;（3）验证危重病患者血浆vWF和sICAM-1水平与ABO血型有关，并介导ABO血型对ARDS危险性的影响;和4）培训和指导申请人的技能，知识，和经验所需的发展成为一个独立的研究者在病人为导向的转化研究。该提案利用宾夕法尼亚大学现有的基础设施，对严重创伤和严重脓毒症患者进行队列研究。既往入组现有队列的受试者和在奖励期间入组的受试者将在确定ABO血型、“分泌型”状态和刘易斯血型的ABO、FUT 2和FUT 3基因的已知多态性进行基因分型。我们将在表型良好的队列中检测这些变异与ARDS风险的相关性。此外，我们将使用因果通路分析来确定vWF和sICAM-1对观察到的ABO和ARDS之间相关性的相对贡献。通过严格的培训计划，涉及研究行为，先进的统计分析和遗传流行病学教学法，以及密集的指导，候选人将获得队列研究设计和开发，遗传和血浆蛋白处理和分析，以及先进的统计技术，包括因果途径和纵向数据分析的技能。他的导师和咨询委员会将通过定期讨论和审查，确保候选人在研究，出版和职业发展方面达到基准。拟议目标和培训计划的实施将使候选人对ARDS病理生理学的理解做出重大贡献，成熟为研究者，并准备成功竞争未来的独立研究资金。

 DESCRIPTION (provided by applicant): The acute respiratory distress syndrome (ARDS) affects an estimated 190,000 people in the US annually, with high mortality and morbidity; however, there are minimal effective pharmacologic therapies for ARDS. Therefore, there is significant interest in identifying novel ARDS risk factors that could lead to future therapeutic targets and identify populations most likely to benefit from such therapies. The ABO gene encodes a family of glycosyltransferases that catalyze specific carbohydrate modifications on cells and characterize the ABO blood group. ABO genetic variation is known to influence risk of infectious and vascular diseases as well as plasma levels of glycoproteins implicated in ARDS, including von Willebrand factor (vWF) and soluble intercellular adhesion molecule-1 (sICAM-1). We recently reported a novel association between blood type A and increased ARDS risk, convergent with prior findings in vascular diseases. The broad objectives of this proposal are to 1) determine the role of ABO genetic variation in altering ARDS risk in cohorts of patients with trauma and severe sepsis; 2) determine the role of functional variation in related genes, FUT2 and FUT3, in ARDS and the role of FUT2 determined "secretor" status in modifying the associations between ABO and ARDS; 3) test the hypothesis that plasma levels of vWF and sICAM-1 are associated with ABO blood type in the critically ill and mediate the affects of ABO blood type on ARDS risk; and 4) train and mentor the applicant in the skills, knowledge, and experience required to develop into an independent investigator in patient oriented translational research. This proposal leverages existing infrastructure at the University of Pennsylvania to conduct cohort studies in patients with major trauma and, separately, severe sepsis. Subjects previously enrolled in existing cohorts and those enrolled during the award period will be genotyped at known polymorphisms in the ABO, FUT2, and FUT3 genes that determine ABO blood types, "secretor" status, and Lewis blood type. These variants will be tested for associations with ARDS risk in our well-phenotyped cohorts. Additionally, we will use causal pathway analyses to determine the relative contribution of vWF and sICAM-1 to observed associations between ABO and ARDS. Through a rigorous training plan involving research conduct, didactics in advanced statistical analysis and genetic epidemiology, and intensive mentorship, the candidate will gain skills in cohort study design and development, genetic and plasma protein processing and analysis, and advanced statistical techniques including causal pathway and longitudinal data analysis. His mentor and advisory committee will ensure the candidate's attainment of benchmarks in research, publication, and career development through regular discussion and review. The conduct of the proposed aims and training plan will allow the candidate to make significant contributions to the understanding of ARDS pathophysiology, mature as an investigator, and prepare to compete successfully for future independent research funding.