Multi-Omics and Mitochondrial Dysfunction in Acute Lung Injury
Abstract
This proposal addresses the Topic Area of “Acute Lung Injury,” utilizing novel approaches (metabolomics, lipidomics, and mass spec imaging) to identify the causes of sepsis-induced acute lung injury (ALI) and biomarkers that differentiate patients at risk of developing ALI from those not at risk. This project also proposes the development and testing of a potential new drug, BTP2, to reduce the incidence and/or severity of ALI. Multiple organ failure (MOF), often precipitated by ALI brought on by sepsis or blunt trauma, is a major cause of death and reduced quality of life in the military theater and in civilian life. In approximately 1/3 of sepsis patients, the inflammation that is a defining feature of sepsis triggers dysfunction of the cells lining the blood vessels in the lungs, which in turn leads to ALI. The concentrations of calcium, both inside the cell and inside the mitochondria, the energy-producing compartments within the cell, act as signals controlling cell health, viability, and function. Changes in mitochondrial calcium concentrations can lead to cell death. Recent studies in humans and animal models show that mitochondria are likely not functioning normally in conditions of sepsis and changes in mitochondrial calcium concentrations may be responsible for this dysfunction. This proposal seeks to identify and characterize the roles of proteins responsible for controlling the concentrations of calcium inside cells and mitochondria, to assess how mitochondria in the cells that line the blood vessels of the lungs are functioning in conditions that model ALI, and to determine if altering the function of the proteins responsible for controlling calcium concentrations inside the cell improves survival in ALI models. We will perform studies in cultured cells and in a mouse model of ALI, and then translate those findings into a pig model of ALI that more closely resembles humans. In all experiments, we will study the health and viability of the cells that line the blood vessels of the lungs and the function of their mitochondria. In the pig models, we will also examine the structure of lung tissue, as well as other tissues that are involved in MOF, including the heart, liver, gut, spleen, kidney, and brain. In all experiments, we will perform new techniques (metabolomics, lipidomics, and mass spec imaging) to assess the metabolism of the cells and tissues to look for markers of mitochondrial dysfunction, which may give clues to how ALI develops and identify ways to differentiate patients at risk of developing ALI from those not at risk. Understanding the molecular pathways that lead from sepsis to ALI to MOF has the potential to significantly reduce the burden of these pathologies. Furthermore, differentiating between patients at risk of progressing from sepsis to ALI from those not at risk through identification of biomarkers of progression will permit more targeted treatment of at-risk patients. Finally, a successful test of a novel therapeutic for ALI in a pig model would move this therapeutic one step closer to testing in humans and in so doing move us one step closer to developing a new treatment for ALI. Given that ALI often leads to MOF and death, the development of a new treatment for ALI has the potential to significantly reduce mortality.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910659
Entities
People
- Kumar Sharma
Organizations
- United States Army
- University of Texas Health Science Center at San Antonio