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

• 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
• 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

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.

描述（由申请人提供）：败血症是重症监护病房中死亡的主要原因。我们的长期目标是了解脓毒症引起的多器官衰竭的机制，并为这种致命疾病寻找潜在的新治疗机会。目前的证据表明线粒体活性氧（mtROS）是脓毒症的主要促进者。在本提案中，我们将使用心脏作为模型系统来研究脓毒症期间 mtROS 的病理反应，并探索该疾病的治疗方案。根据文献和我们的初步研究，我们假设，在心脏中，败血症诱导的 mtROS 过量产生会引发适应不良的自噬，这在刺激过度炎症和心脏功能障碍中发挥着关键作用。我们进一步假设，通过线粒体靶向抗氧化剂（MTA）增强 mtROS 特异性防御​​可能为脓毒症提供显着的治疗益处。我们将结合分子生物学、生物化学、组织学和生理学评估的方法，使用体外和体内脓毒症模型来测试这些假设。这些研究包括通过 mtROS 确定心脏自噬的机制（目标 1），检查自噬是否是一种适应不良反应（目标 2），以及 MTA 在败血症中的治疗潜力的临床前评估（目标 3）。我们期望这些研究将增进对脓毒症病理学的理解，并且 MTA 的评估将提供重要的转化意义。