Pathological Responses to Mitochondrial ROS in Sepsis-Induced Cardiac Dysfunction

描述(由申请人提供)：败血症是重症监护病房的主要死亡原因。我们的长期目标是了解脓毒症引起多器官衰竭的机制，并确定这种致命疾病的潜在新治疗机会。目前的证据表明，线粒体活性氧簇(MtROS)在脓毒症中起着主要的促进剂作用。在这项提案中，我们将使用心脏作为一个模型系统来研究脓毒症期间mtROS的病理反应，并探索这种疾病的治疗方案。根据文献和我们的初步研究，我们假设，在心脏中，脓毒症诱导的mtROS过量产生触发了适应性不良的自噬，这在刺激过度炎症和心功能障碍中起着关键作用。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著的治疗益处。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检验这些假说。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不良适应反应(目标2)，以及MTA在脓毒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促进对脓毒症病理的理解，对MTA的评估将提供重要的翻译意义。

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.