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.

Public Health Relevance

The acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure with a high morbidity and mortality and frequently complicates severe infections that result in sepsis. An individuals'ABO blood type is genetically determined and has been identified as a risk factor for various infectious and vascular diseases. The aim of this research is to provide new knowledge about the role of ABO blood type as a risk factor for ARDS and to elucidate pathways that result in this relationship.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F10A-S (20))
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Colombini-Hatch, Sandra
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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Shashaty, Michael G S; Reilly, John P; Sims, Carrie A et al. (2016) Plasma Levels of Receptor Interacting Protein Kinase-3 (RIP3), an Essential Mediator of Necroptosis, are Associated with Acute Kidney Injury in Critically Ill Trauma Patients. Shock 46:139-43
Reilly, John P; Anderson, Brian J; Hudock, Kristin M et al. (2016) Neutropenic sepsis is associated with distinct clinical and biological characteristics: a cohort study of severe sepsis. Crit Care 20:222
Reilly, John P; Christie, Jason D (2015) Primed for Injury: Cigarette Smokers and Acute Respiratory Distress Syndrome. Crit Care Med 43:2015-6
Reilly, John P; Anderson, Brian J; Mangalmurti, Nilam S et al. (2015) The ABO Histo-Blood Group and AKI in Critically Ill Patients with Trauma or Sepsis. Clin J Am Soc Nephrol 10:1911-20