Improving Mitochondrial Function to Protect against Myocardial Ischemia/Reperfusion

改善线粒体功能以防止心肌缺血/再灌注

基本信息

批准号：
9908162
负责人：
QINGLIN YANG
金额：
$ 36.75万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-05 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9908162
关键词：
ATP Hydrolysis ATP Synthesis Pathway Adenoviruses Affect Attenuated Biochemical Cardiac Cardiac Myocytes Cardiac Surgery procedures Cardiomyopathies Cardiovascular system Chickens Clinical Congestive Heart Failure Coupling Defect Dependovirus Disease Down Syndrome Energy Metabolism Enhancers Enzymes Escherichia coli Gene Targeting Generations Genes Heart Impairment In Vitro Ischemia Knock-out Knockout Mice Lead Mediating Metabolic Mitochondria Mitochondrial Proteins Mitochondrial Proton-Translocating ATPases Molecular Morphology Multienzyme Complexes Mus Myocardial Myocardial Infarction Myocardial Ischemia Myocardium Names Organ Outcome Oxidation-Reduction Oxidative Phosphorylation PPAR alpha Patients Performance Peroxisome Proliferator-Activated Receptors Pilot Projects Play Production Proteins Protons Regulation Reperfusion Injury Reperfusion Therapy Reservations Respiration Role Satellite Viruses Serotyping Signal Transduction Skeletal Muscle Structure Tamoxifen Testing Therapeutic Tissues Transgenic Organisms Troponin T Viral Vector Work base gain of function gene therapy genetic manipulation genomic locus heart metabolism human disease improved in vivo innovation insight ischemic cardiomyopathy mitochondrial membrane mitochondrial metabolism mouse model new therapeutic target novel overexpression pre-clinical prevent promoter success therapeutic gene

项目摘要

Myocardial ischemia/reperfusion (IR) injury is the main clinical challenge of adverse cardiovascular outcomes after myocardial ischemia, cardiac surgery or circulatory arrest. It is well established that myocardial ATP depletion is a key feature of myocardial ischemia and heart failure1. Improving myocardial energy metabolism has been a well- known target to protect the heart from IR injury, but with little success. " ATP synthase is a key enzyme complex generating ATP in mitochondria, thus playing a central role in mitochondrial function. Functional defects of ATP synthase can cause and aggravate human diseases, such as cardiomyopathy and congestive heart failure. However, our understanding of the regulation of energy metabolism and mitochondrial function in the energy demanding heart remains poor. We have recently identified a PPAR-target gene encoding a novel mitochondrial protein ES1 with unknown function. Preliminary studies revealed that ES1 is a mitochondrial protein interacting with the subunits α and β of ATP synthase F1 sector. We were excited to find that ES1 works as an enhancer of ATP production by increasing ATP synthesis and inhibiting ATP hydrolysis. However, it remains unknown if ES1 similarly regulates ATP production in the heart subjected to myocardial IR. Interestingly, our preliminary studies revealed that ES1 protein levels were decreased in hearts with myocardial IR injury of patients and mice. Based on the pilot studies on conditional transgenic and gene targeting mouse lines, we hypothesize that ES1 is a novel therapeutic target of protecting the heart from myocardial IR via its role in facilitating cardiac energy production/reservation. To test this central hypothesis, we will first define the role of ES1 as an endogenous regulator of ATP synthase and as a determinant of mitochondrial structure/function in the heart. We will then determine if transgenic and adenoviral-associated virus-mediated ES1 overexpression in the heart protects the heart against myocardial IR injury by its role in regulating energy metabolism. These studies will provide novel insights into how to manipulate energy metabolism to protect the heart from myocardial IR injury. Furthermore, these new fundamental scientific findings will have broader implications in diseases related to other organs and tissues.

心肌缺血/再灌注（IR）损伤是不良反应的主要临床挑战心肌缺血、心脏手术或停循环后的心血管结局。众所周知，心肌 ATP 耗竭是心肌病的一个关键特征。改善心肌能量代谢一直是缺血和心力衰竭的一个很好的方法。保护心脏免受红外线损伤的已知目标，但收效甚微。 ATP合酶是线粒体中产生ATP的关键酶复合物，因此发挥着 ATP合酶的功能缺陷可导致线粒体功能的核心作用。加重人类疾病，如心肌病和充血性心力衰竭。然而，我们对能量代谢和线粒体调节的理解我们最近发现了一个需要能量的心脏的功能仍然很差的情况。 PPAR 靶基因编码功能未知的新型线粒体蛋白 ES1。初步研究表明，ES1是一种与线粒体相互作用的线粒体蛋白。我们很高兴地发现 ES1 发挥着 ATP 合酶 F1 亚基的作用。通过增加 ATP 合成和抑制 ATP 来增强 ATP 生成然而，ES1 是否同样调节 ATP 的产生仍不清楚。心脏受到心肌IR有意义，我们的初步研究表明ES1。心肌IR损伤的患者和小鼠心脏中蛋白质水平下降。基于条件转基因和基因靶向小鼠品系的初步研究，我们 ES1 是保护心脏免受损害的新治疗靶点心肌 IR 通过其促进心脏能量产生/储备的作用。为了检验这个中心假设，我们首先将 ES1 的作用定义为内源性 ATP 合成酶的调节剂，并作为线粒体结构/功能的决定因素然后我们将确定转基因和腺病毒相关病毒是否介导。 ES1 在心脏中的过度表达可通过其保护心脏免受心肌 IR 损伤这些研究将为调节能量代谢提供新的见解。操纵能量代谢以保护心脏免受心肌IR损伤。此外，这些新的基础科学发现将在以下方面产生更广泛的影响：与其他器官和组织有关的疾病。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

ATP synthase inhibitory factor subunit 1 regulates islet β-cell function via repression of mitochondrial homeostasis.

ATP 合成酶抑制因子亚基 1 通过抑制线粒体稳态来调节胰岛 β 细胞功能。

DOI：
发表时间：
2022-01
期刊：
影响因子：
0
作者：
Zhang, Kailiang;Bao, Rong;Huang, Fengyuan;Yang, Kevin;Ding, Yishu;Lauterboeck, Lothar;Yoshida, Masasuke;Long, Qinqiang;Yang, Qinglin
通讯作者：
Yang, Qinglin

ATP synthase inhibitory factor subunit 1 regulates islet β-cell function via repression of mitochondrial homeostasis.

ATP 合成酶抑制因子亚基 1 通过抑制线粒体稳态来调节胰岛 β 细胞功能。

DOI：
发表时间：
2022-01
期刊：
影响因子：
0
作者：
Zhang, Kailiang;Bao, Rong;Huang, Fengyuan;Yang, Kevin;Ding, Yishu;Lauterboeck, Lothar;Yoshida, Masasuke;Long, Qinqiang;Yang, Qinglin
通讯作者：
Yang, Qinglin

Nischarin Deletion Reduces Oxidative Metabolism and Overall ATP: A Study Using a Novel NISCHΔ5-6 Knockout Mouse Model.

Nicharin 缺失减少氧化代谢和总体 ATP：使用新型 NISCHα5-6 敲除小鼠模型的研究。

DOI：
发表时间：
2022-01-25
期刊：
影响因子：
5.6
作者：
Nguyen, Tina H;Yousefi, Hassan;Okpechi, Samuel C;Lauterboeck, Lothar;Dong, Shengli;Yang, Qinglin;Alahari, Suresh K
通讯作者：
Alahari, Suresh K

Real-Time Visualization of Cytosolic and Mitochondrial ATP Dynamics in Response to Metabolic Stress in Cultured Cells.

实时可视化细胞质和线粒体 ATP 动态响应培养细胞中的代谢应激。

DOI：
发表时间：
2023-02-22
期刊：
影响因子：
6
作者：
White 3rd, Donnell;Lauterboeck, Lothar;Mobasheran, Parnia;Kitaguchi, Tetsuya;Chaanine, Antoine H;Yang, Qinglin
通讯作者：
Yang, Qinglin

IF1 Promotes Cellular Proliferation and Inhibits Oxidative Phosphorylation in Mouse Embryonic Fibroblasts under Normoxia and Hypoxia.

常氧和缺氧条件下，IF1 可促进小鼠胚胎成纤维细胞的细胞增殖并抑制氧化磷酸化。

DOI：
发表时间：
2024-03-21
期刊：
影响因子：
6
作者：
Lauterboeck, Lothar;Kang, Sung Wook;White 3rd, Donnell;Bao, Rong;Mobasheran, Parnia;Yang, Qinglin
通讯作者：
Yang, Qinglin