权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Autophagy-dependent cardioprotection in ischemia/reperfusion injury

缺血/再灌注损伤中自噬依赖性心脏保护作用

基本信息

批准号：
9262983
负责人：
Min Xie
金额：
$ 16.79万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9262983
关键词：
Alpha Cell Animal Model Area Autophagocytosis Biological Assay Blood flow Cardiac Myocytes Cell Death Cell physiology Clinical Clinical Trials Data Engineering Event Eye Fluorescence Genes HDAC1 gene Histone Deacetylase Human In Vitro Infarction Ischemia Knockout Mice Knowledge Lead Measures Mitochondria Modeling Molecular Morbidity - disease rate Morphology Mus Myocardial Infarction Myocardial Ischemia Myocardium Pathway interactions Peptides Permeability Physicians Process Production Publications Quality Control RNA Interference Recycling Regulation Reperfusion Injury Reperfusion Therapy Research Role Scientist Stress Testing Therapeutic Therapeutic Agents Time Training Transgenic Mice Ventricular Function Vorinostat acute coronary syndrome clinical translation in vivo injured knock-down mortality myocardial infarct sizing novel novel therapeutics public health relevance response restoration targeted treatment tool translational approach

项目摘要

DESCRIPTION (provided by applicant): Rapid restoration of blood flow to the ischemic heart is vital in acute coronary syndromes. However, reperfusion also contributes significantly to myocardial infarct size(1). Currently, there are no clinical therapies targeting reperfusion injury Elucidation of mechanisms of reperfusion injury -- with an eye toward clinical translation -- is urgently needed. Inhibition of class 1 histone deacetylases (HDACs), specifically at the time of reperfusion, confers cardioprotection in multiple animal models of ischemia/reperfusion (I/R) injury(2, 3). Autophagy is critical in the response to I/R injury(3). We have demonstrated that HDAC inhibition promotes cardiomyocyte autophagy, which is critical to the robust cardioprotective effects we observe(3). Also, appropriate mitochondrial quality control is critical to cardioprotection during I/R(4, 5). Here, we will define mechanisms whereby cardiomyocyte autophagy protects against I/R injury. We propose to manipulate autophagy using two strategies: a) HDAC inhibition, and b) a cell-permeable peptide (Tat-Beclin), a strong autophagy activator(6). The former approach is imminently translatable to the clinical context. The latter approach allows us to isolate specifically the contribution of activated autophagy, parsing it from other effects of HDAC inhibition. Also, we will define mechanisms whereby activated autophagy is protective, focusing on excessive ROS production by defective mitochondria escaping autophagic elimination. We hypothesize that Tat-Beclin treatment will promote autophagy and confer cardioprotection to reperfusion-injured myocardium. We also hypothesize that induction of autophagy either with HDAC inhibition or Tat-Beclin will lead to a decrease in ROS production during reperfusion in the border zone resulting in increased cardiomyocyte survival. Aim 1: Determine whether Tat-Beclin induces autophagy and whether it is cardioprotective in I/R- stressed cardiomyocytes in vitro. Aim 2: Determine whether Tat-Beclin is cardioprotective in an in vivo cardiac I/R injury model and whether autophagy is essential for the cardioprotection. Aim 3: Determine whether therapeutically up-regulated cardiomyocyte autophagy preserves mitochondrial function and reduces ROS production. This proposal is timely, mechanistic, novel, and holds great potential to reduce morbidity and mortality in ischemic heart disease. Tat-Beclin, a selective autophagy inducer, is a powerful way to extend our understanding of autophagy-dependent cardioprotection in I/R injury. Further, we will explore cardioprotective reperfusion targets in the autophagic pathway, such as ROS regulation. As Tat-Beclin is a potential therapeutic agent, this is a uniquely translational strategy with potential for clinical impact. Finally, this research serves as a critical platform for me to complete my training as a physician-scientist.