Pathological Responses to Mitochondrial ROS in Sepsis-Induced Cardiac Dysfunction

脓毒症引起的心脏功能障碍中线粒体 ROS 的病理反应

基本信息

批准号：
8747376
负责人：
Qun Sophia Zang
金额：
$ 29.07万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-25 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8747376
关键词：
American Antibiotic Therapy Antioxidants Attenuated Autophagocytosis Biochemistry Biological Models Cardiac Cardiac Myocytes Cause of Death Cell Culture Techniques Clinical Clinical Research Critical Care Data Disease Disease model Down-Regulation Drug Targeting Evaluation Experimental Designs Functional disorder Future Goals Heart Heart failure Histology IV Fluid In Vitro Inflammation Injury Intensive Care Investigation Knock-out Link Lipopolysaccharides Literature Mediating Mitochondria Modeling Molecular Biology Mus Myocardial Natural Immunity Neonatal Organ Organ failure Outcome Pathogenesis Pathology Patient Care Patients Performance Pharmaceutical Preparations Physiology Play Pneumonia Process Production Rattus Reactive Oxygen Species Reporter Research Role SOD2 gene Sepsis Superoxide Dismutase Supportive care Testing Therapeutic Translations Treatment Efficacy Up-Regulation base bench to bedside clinically relevant effective therapy improved in vitro Model in vivo killings mortality mouse model new therapeutic target novel novel therapeutic intervention novel therapeutics overexpression pre-clinical preclinical evaluation promoter public health relevance response

项目摘要

DESCRIPTION (provided by applicant): 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.