The impact of glycocalyx degradation on ARDS pathogenesis and outcomes - PROJECT SUMMARY Background: Acute respiratory distress syndrome (ARDS) affects over 200,000 US patients per year and has a 30-40% mortality rate. Numerous attempts to develop effective therapies for ARDS have failed, which is increasingly attributed to substantial patient-level mechanistic heterogeneity. This heterogeneity has inspired efforts to identify “treatable traits” in ARDS: causal mechanisms that can be identified and targeted to produce meaningful benefit to patients. The pulmonary endothelial and epithelial glycocalyces are glycosaminoglycan- enriched layers that line the lung vasculature and airspaces respectively. Glycocalyx degradation contributes to lung injury in mice, and biomarkers of glycocalyx degradation are associated with worse outcomes in ARDS patients. These data suggest that glycocalyx degradation may be a treatable trait in ARDS. The proposed research will estimate the attributable impact of glycocalyx degradation on ARDS outcomes and determine the longitudinal relationship between glycocalyx degradation and the dynamic physiology of ARDS, thereby establishing a framework to translate these mechanistic discoveries into effective therapies. Candidate: Dr. Alicia Rizzo is a pulmonary and critical care physician at Massachusetts General Hospital (MGH) with prior PhD training in the molecular pathogenesis of ARDS. Her career goal is to establish a patient-oriented research program that will utilize airspace and circulating biomarkers of glycocalyx dysfunction to inform the execution of precision medicine strategies in ARDS. To accomplish this goal she has assembled a team of mentors within the world-class research environment at MGH. Mentorship: Dr. Eric Schmidt (primary mentor) is an NIH-funded investigator who conducts mechanistic research on the glycobiology of ARDS. He has mentored 2 NIH K awardees, who both currently run independent research programs. Co-mentorship from Drs. Taylor Thompson (ARDS clinical research) and Marie-Abéle Bind (biostatistics) will provide additional training that will enable Dr. Rizzo to develop a skillset that is distinct from that of her primary mentor. Research: Dr. Rizzo will enroll 200 ARDS patients in a prospective cohort study at MGH, which will include patient-level data, longitudinal bedside physiologic assessments, and serial biospecimen collection (airspace fluid and plasma). She will employ causal inference approaches to estimate the attributable impact of glycocalyx degradation on patient outcomes (Aim 1) and longitudinal modeling to determine the relationship between glycocalyx degradation and the dynamic physiology of ARDS (Aim 2). Training: Dr. Rizzo will pursue training in 1) ARDS cohort studies, 2) structural glycobiology, and 3) advanced biostatistics (causal inference methodology and longitudinal modeling), which will include mentored experiential learning and didactics at the Harvard T.H. Chan School of Public Health. Summary: This K23 will enable Dr. Rizzo to make significant contributions to our understanding of the glycobiology of ARDS and transition to independence as a patient-oriented researcher focused on developing glycan-targeted precision medicine strategies for patients with ARDS.
