Beclin-1 in Sepsis-Induced Cardiac Dysfunction

Beclin-1 在脓毒症引起的心脏功能障碍中的作用

• 批准号: 10225148
• 负责人: Qun Sophia Zang
• 金额: $ 18.03万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10225148
• 关键词: Beclin; Sepsis; Induced; Cardiac; Dysfunction

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.

项目摘要 败血症是由失调的宿主引起的器官功能障碍的生命状况 对感染的反应。我们的研究重点是理解 败血症引起的心肌病，其最终目的是开发新疗法。 在我们最近发表的流通研究（2018年5月）中，我们获得了有力的证据 表明自噬的核心调节剂Beclin-1可减轻炎症和 在内毒素血症期间改善心脏功能。我们假设Beclin-1是 败血症引起的心脏功能障碍的预期新的和关键的治疗靶标。在 该应用，我们将使用遗传和药理检验该假设 体外和体内败血症模型的接近。我们将确定 Beclin-1如何通过线粒体相关的调节途径保护心脏 膜（AIM 1）和通过选择性诱导自适应线粒体（AIM 2） 败血症。我们将进一步进行全面的临床前评估 在临床相关模型中开发了Beclin-1激活肽（AIM 3）。我们期望 这些调查不仅会提高对败血症的基本理解 发病机理，但也确定了一种具有有希望改善潜力的新型疗法 败血症的患者护理质量和临床结果。