Sepsis is a leading cause of death in critical care units. Our long-term goal is to understand the mechanisms of sepsis-induced multi-organ failure and to identify potential new therapeutic opportunities for this deadly disease. Current evidence suggests that mitochondrial reactive oxygen species (mtROS) function as a major promoter in sepsis. In this proposal, we will use the heart as a model system to study the pathological responses to mtROS during sepsis and to explore therapeutic options for this disease. Based on literature and our preliminary investigations, we hypothesize that, in the heart, sepsis-induced overproduction mtROS triggers maladaptive autophagy, which plays a critical role in stimulating excessive inflammation and cardiac dysfunction. We further hypothesize that enhancing mtROS-specific defense by mitochondria-targeted antioxidants (MTAs) may provide significant therapeutic benefits for sepsis. We will test these hypotheses using both in vitro and in vivo sepsis models by combining approaches of molecular biology, biochemistry, histology, and physiology assessments. The studies involve determination of the mechanism underlying cardiac autophagy through mtROS (Aim 1), examination of whether autophagy is a maladaptive response (Aim 2), and preclinical evaluation of the therapeutic potential of MTAs in sepsis (Aim 3). We expect that these investigations will advance the understanding of sepsis pathology and the evaluation of MTAs will provide important translational implications.

Public Health Relevance

Sepsis is a deadly disease that kills approximately 215,000 Americans each year. In this proposal, we will use sepsis disease models to investigate the mechanisms underlying sepsis-associated heart failure and to test whether a novel class of antioxidants, which specifically target against mitochondrial reactive oxygen species (mtROS), can improve sepsis outcomes. Our investigation will provide a preclinical evaluation for new drugs that may potentially improve the clinical outcomes of patients with sepsis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM111295-01
Application #
8747376
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Dunsmore, Sarah
Project Start
2014-09-25
Project End
2019-08-31
Budget Start
2014-09-25
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$290,700
Indirect Cost
$110,700
Name
University of Texas Sw Medical Center Dallas
Department
Surgery
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390