ABO Glycosyltransferases in Sepsis Associated Acute Respiratory Distress Syndrome

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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.