Beclin-1 in Sepsis-Induced Cardiac Dysfunction

项目摘要 脓毒症是一种危及生命的器官功能障碍的情况下所造成的失调主机 对感染的反应。我们的研究重点是了解 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， 改善内毒素血症期间的心脏功能。我们假设Beclin-1是一种 脓毒症引起的心功能不全的前瞻性新的和关键的治疗靶点。在 在本申请中，我们将使用遗传和药理学方法来验证这一假设。 方法在体外和体内脓毒症模型。我们将确定 Beclin-1是如何通过调节途径通过与心脏相关的 膜（目的1）和选择性诱导适应性线粒体自噬（目的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了Beclin-1-活化肽（目的3）。我们预计 这些研究不仅会促进对败血症的基本认识， 发病机制，而且还确定了一种新的治疗方法，有希望改善 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.