Beclin-1 in Sepsis-Induced Cardiac Dysfunction

项目摘要 脓毒症是一种由失控的宿主引起的危及生命的器官功能障碍。 对感染的反应。我们的研究集中在了解心力衰竭的机制。 败血症引起的心肌病，最终目标是开发新的治疗方法。 在我们最近发表在《循环》(2018年5月)上的研究中，我们获得了强有力的证据 显示Beclin-1，自噬的核心调节因子，减轻炎症和 改善内毒素血症时的心功能。我们假设Beclin-1是一个 脓毒症所致心功能障碍的前瞻性新的关键治疗靶点。在……里面 在这个应用中，我们将使用遗传学和药理学来检验这一假说 体外和体内脓毒症模型的研究进展。我们将确定其机制。 Beclin-1如何通过线粒体相关的调控途径保护心脏 膜(目标1)和选择性诱导适应性有丝分裂吞噬(目标2) 败血症。我们将进一步对一种新的 在临床相关模型中开发Beclin-1激活肽(目标3)。我们预计 这些研究不仅将促进对脓毒症的基本了解 发病机制，但也确定了一种具有改进潜力的新疗法 脓毒症的患者护理质量和临床结局。

Project Summary Sepsis is a life-threatening condition of organ dysfunction caused by a deregulated host response to infection. Our research is focused on understanding the mechanisms of sepsis-induced cardiomyopathy, with an ultimate goal of developing new therapies. In our recently published study in Circulation (May, 2018), we obtained strong evidence showing that Beclin-1, a core regulator of autophagy, mitigates inflammation and improves cardiac function during endotoxemia. We hypothesize that Beclin-1 is a prospective new and key therapeutic target for sepsis-induced cardiac dysfunction. In this application, we will test this hypothesis using both genetic and pharmacological approaches in sepsis models in vitro and in vivo. We will determine the mechanisms of how Beclin-1 protects the heart by a regulatory pathway via mitochondria-associated membranes (aim 1) and by a selective induction of adaptive mitophagy (aim 2) during sepsis. We will further perform a comprehensive preclinical evaluation for a newly developed Beclin-1-activating peptide in clinically relevant models (aim 3). We expect that these investigations will not only advance the fundamental understanding of sepsis pathogenesis, but also identify a novel therapy with promising potential to improve patient care quality and clinical outcomes for sepsis.