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

基本信息

批准号：
10474457
负责人：
Qun Sophia Zang
金额：
$ 30.8万
依托单位：
LOYOLA UNIVERSITY CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-25 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10474457
关键词：
Animal Model Animals Attenuated Autophagocytosis Blood Circulation Cardiac Cardiomyopathies Cause of Death Cells Clinical Critical Care Data Dependence Endoplasmic Reticulum Endotoxemia Foundations Functional disorder Future Genetic Genetic Models Goals Health Heart Immune response Impairment Infection Inflammation Investigation Life Mediating Medical Membrane Mitochondria Modeling Molecular Myocardial Myocardial dysfunction Myocardium Organ Outcome PINK1 gene Parkin Pathogenesis Pathologic Pathway interactions Patient Care Pattern Peptides Permeability Pharmacology Publishing Quality Control Quality of Care Regulation Regulatory Pathway Research Role Sepsis Signal Transduction Solid Testing Therapeutic Treatment Efficacy cecal ligation puncture clinically relevant drug development effective therapy heart function improved in vitro Model in vivo loss of function novel novel therapeutics peptide B pneumonia model polymicrobial sepsis preclinical evaluation prospective proteomic signature recruit septic therapeutic target ubiquitin-protein ligase

项目摘要

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。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Biomarkers and molecular endotypes of sarcoidosis: lessons from omics and non-omics studies.

DOI：
10.3389/fimmu.2023.1342429
发表时间：
2023
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
通讯作者：

Beclin-1 dependent autophagy improves renal outcomes following Unilateral Ureteral Obstruction (UUO) injury.

DOI：
10.3389/fimmu.2023.1104652
发表时间：
2023
期刊：
FRONTIERS IN IMMUNOLOGY
影响因子：
7.3
作者：
Lopez-Soler, Reynold I. I.;Nikouee, Azadeh;Kim, Matthew;Khan, Saman;Sivaraman, Lakshmi;Ding, Xiangzhong;Zang, Qun Sophia
通讯作者：
Zang, Qun Sophia

Mitochondrial ROS Induces Cardiac Inflammation via a Pathway through mtDNA Damage in a Pneumonia-Related Sepsis Model.