Investigating the Role of Vascular Injury and Physiologic Dead Space in the Acute Respiratory Distress Syndrome

Project Summary This is an application for a K23 award for Ana Monteiro, MD, PhD, a Pulmonary and Critical Care physician at the University of California Los Angeles. The goal of this proposal is for Dr. Monteiro to establish herself as a young investigator in patient-oriented research of acute respiratory distress syndrome (ARDS), with a focus on vascular injury as a contributor to pulmonary physiologic dysfunction and worse outcomes in ARDS. This K23 award will provide Dr. Monteiro with the support necessary to: 1) study the biologic endotype of ARDS involving vascular injury, pulmonary physiologic dysfunction and worsening mortality; 2) determine the feasibility and utility of measuring peripheral blood markers to determine pulmonary disease severity; 3) become an expert in analysis of large datasets of both clinical and transcriptomic nature; 4) become proficient in the use of bulk and single cell transcriptomic analysis; 5) become an expert clinical and translational researcher in ARDS; and 6) develop an independent translational research career. Dr. Monteiro’s plan to achieve these goals is supported by a multidisciplinary mentoring team of experts. Her primary mentors, Drs. Michael Matthay and Anil Sapru, have extensive experience in translational ARDS research and in the career development of early-stage investigators. Dr. Monteiro will also work with Dr. Matteo Pellegrini, a bioinformatics expert and world leader on the science of bulk and single cell transcriptomics, Dr. John Belperio, an expert in post- transplant primary graft dysfunction with extensive experience with biospecimen handling and biobanking and a recognized pulmonary educator, Dr. Steve Dubinett, a world class clinical and translational researcher of cancer immunology, and Sitaram Vangala, the Director of the Medicine Biostatistics core and an expert in causal inference. ARDS is characterized by an increased inflammatory response that induces epithelial and vascular damage and respiratory failure. This proposal will investigate the causal pathways connecting vascular injury to respiratory failure by utilizing previously collected data and plasma samples from the completed ROSE-PETAL network trial and the ongoing observational cohort study (LOBAR) that will prospectively collect biospecimens, mechanical ventilation data, and clinical outcomes. This proposal represents an innovative approach by addressing the feasibility and utility of evaluating proteomic, transcriptomic and cell-level blood markers including circulating endothelial cells in identifying novel pathological pathways and determine pulmonary disease severity. The Specific Aims are: 1) Test whether local or systemic markers of endothelial injury best predict lung dysfunction and mortality in ARDS; 2) Leverage bulk RNA sequencing of blood to characterize and quantify endothelial damage in ARDS; and 3) An exploratory aim to characterize biological derangement of CECs in ARDS using cell-level transcriptomic analysis. Addressing these gaps in knowledge may promote non-invasive analytic techniques for future ARDS studies and reveal novel pathways in ARDS pathogenesis for therapeutic targeting. The research and training outlined in this proposal will form the basis for an R01-level proposal designed to study interventions tailored to patients with a vascular injury predominant endotype of ARDS.