Proteomic and metabolomic trajectories of ARDS molecular phenotypes

University Of California, San Francisco, San Francisco CA

Investigators

Abstract

ABSTRACT. This application is for a K23 award for Narges Alipanah-Lechner, MD, MAS, a Clinical Instructor in the Division of Pulmonary/Critical Care Medicine at the University of California San Francisco. Dr. Alipanah- Lechner is a young investigator in patient-oriented translational research in the acute respiratory distress syndrome (ARDS). This proposal will allow her to achieve competency in computational methods for high throughput data analyses and advanced epidemiologic methods, develop expertise in conducting prospective observational studies, enhance her understanding of systems biology, and become an independent investigator. To achieve these objectives, the candidate has assembled a mentoring team that includes her primary mentor Dr. Carolyn Calfee, renowned expert in ARDS biological subtypes and translational research, Dr. Angela Rogers, co-mentor and expert in metabolomics in critical illness, Dr. Kathleen Stringer, expert in metabolomic methodology and pharmaco-metabolomics, Dr. Gabriela Fragiadakis, expert in bioinformatics, and Dr. Kevin Delucchi, expert in biostatistics. ARDS is a common cause of respiratory failure in the intensive care unit with a high mortality rate and limited treatment options. Recent studies on select plasma proteins have revealed two subtypes of ARDS, termed hyper-inflammatory and hypo-inflammatory, with vastly different mortality outcomes and varying responses to treatments previously considered ineffective. However, little is known about the evolution of these subtypes, whether inflammation is the sole driver of subtype differences, and if they reflect differences in local lung injury. The candidate’s long-term goal is to apply complementary systems biology approaches within precision medicine to improve the diagnosis and treatment of patients with ARDS. The overall objective for this application is to identify metabolite and protein drivers of ARDS evolution in patients with hyper- and hypo-inflammatory ARDS. The central hypothesis, guided by the candidate’s preliminary findings, is that alveolar injury leads to systemic mitochondrial metabolic dysregulation in hyper- inflammatory ARDS but remains limited to the lungs in hypo-inflammatory ARDS. Aim 1 will test whether mitochondrial metabolic dysregulation drives differences between the two ARDS subtypes via comprehensive metabolic profiling of plasma samples from patients previously enrolled in a randomized controlled trial. Aim 2 will investigate plasma protein and metabolite trajectories in patients with hyper- and hypo-inflammatory ARDS in a prospective cohort study that the candidate will conduct. Using the same cohort, Aim 3 will investigate metabolite trajectories in respiratory samples in patients with hyper- and hypo-inflammatory ARDS. This proposal is significant because it will identify molecular pathways of injury and recovery that could serve as therapeutic targets in ARDS patients. These studies will also provide the candidate with data needed to prepare an R01 application focused on understanding how metabolomics in plasma and lungs provides mechanistic insights into the pathogenesis and outcomes of ARDS.