MAVS protein: A role of mitochondria in innate immunity and cardioprotection

MAVS 蛋白：线粒体在先天免疫和心脏保护中的作用

• 批准号: 8268988
• 负责人: Toshitaka Yajima
• 金额: $ 38.24万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8268988
• 关键词: Acute; Antiviral Agents; Apoptosis; Cardiac; Cardiac Myocytes; Cardiomyopathies; Defense Mechanisms; Dilated Cardiomyopathy; Drug toxicity; Germ Lines; Goals; Health; Heart; Heart Diseases; Homeostasis; Host Defense Mechanism; IRF3 gene; Immune; Infection; Interferon Type I; Interferons; Ischemia; Knockout Mice; Link; MAPK Signaling Pathway Pathway; Mass Spectrum Analysis; Mediating; Methods; Mitochondria; Mitochondrial Proteins; Modeling; Molecular; Muscle Cells; Myocardial Ischemia; Myocarditis; Natural Immunity; Oxidative Stress; Phenotype; Physiological; Play; Predisposition; Protein Family; Proteins; Proteomics; Reperfusion Injury; Role; Screening procedure; Signal Pathway; Signal Transduction; Signaling Protein; Stress; Testing; Time; Transgenic Mice; Two-Dimensional Gel Electrophoresis; Virus; Virus Diseases; Yeasts; biological adaptation to stress; mouse model; new therapeutic target; novel; pathogen; pressure; type I interferon receptor; yeast two hybrid system

DESCRIPTION (provided by applicant): The overall aim of this project is to determine the role of a novel mitochondrial protein, mitochondrial antiviral signaling (MAVS) in the cardiac myocyte when the myocyte is exposed to various devastating conditions such as virus infection, acute pressure overload, ischemia, and drug toxicity. MAVS protein has been found to be a key molecule in innate antiviral defense and highlighted a novel function of mitochondria in host defense mechanisms. Since mitochondria have been implicated in cardioprotection against various stresses, the discovery of MAVS protein suggested the presence of unidentified crosstalk between antivirus and cardioprotection mechanisms that involve the mitochondria within the cardiac myocyte. Accordingly, here we will dissect cardiac-specific innate antiviral defense mechanisms mediated through MAVS, and examine the implication of the mechanisms in cardioprotection during various stress responses. Furthermore, we try to identify novel MAVS interacting molecules that are involved in the cardiac-specific innate defense mechanisms. This will contribute to our long-term goal of understanding the molecular mechanisms by which the cardiac myocytes defend themselves against various stresses and maintain homeostasis for a long period of time. Elucidation of the mechanisms will identify novel therapeutic targets that may be beneficial for the treatment of a broad range of cardiac diseases such as virus-mediated cardiomyopathy, dilated cardiomyopathy, ischemic heart disease and toxic cardiomyopathy. Accordingly, we propose the following specific aims: 1. Determine whether MAVS can induce an antiviral effect in the heart that is independent of type I IFN signaling. This will be done by examining the effect of cardiac-specific disruption of 1) MAVS and 2) type I IFN receptor on cardiac myocyte susceptibility to CVB3 infection. 3)The importance of MAVS-dependent but type I IFN-independent antiviral defense mechanisms in the cardiac myocyte will be determined by comparing the phenotype of cardiac-specific MAVS and type I IFN receptor double knockout mice with that of cardiac-specific MAVS or type I IFN receptor single knockout mice post CVB3 infection. 2. Determine whether MAVS has a physiologic or pathophysiologic role on cardiac function using ischemia-reperfusion (I/R) injury as a model for oxidative stress. This will be done by examining the phenotype of germ-line and cardiac-specific MAVS knockout mice under I/R injury. 1)The interaction of MAVS with Bcl-2 family proteins other than Bax as well as CARD-containing proteins other than RIG-I and MDA-5 under I/R injury and 2) The effect of MAVS on NF-:B, IRF3, IRF7, gp130, Akt and MAPK signaling pathway under I/R injury will also be determined. 3. Identify novel adaptor molecules that connect MAVS to downstream innate defense mechanisms by 1) a proteomics approach using two-dimensional gel electrophoresis and mass spectrometry, and 2) the yeast two-hybrid screening method. PUBLIC HEALTH RELEVANCE: This project will contribute to our long-term goal of understanding the molecular mechanisms by which the cardiac myocytes defend themselves when they expose to various devastating conditions such as virus infection, ischemia and drug toxicity. Elucidation of the mechanisms will identify novel therapeutic targets that may be beneficial for the treatment of a broad range of cardiac diseases such as virus-mediated cardiomyopathy, dilated cardiomyopathy, ischemic heart disease and toxic cardiomyopathy.

描述（由申请人提供）：该项目的总体目标是确定当心肌细胞暴露于各种破坏性条件（例如病毒感染、急性压力）时，新型线粒体蛋白、线粒体抗病毒信号传导（MAVS）在心肌细胞中的作用超负荷、缺血和药物毒性。 MAVS 蛋白被发现是先天抗病毒防御的关键分子，并强调了线粒体在宿主防御机制中的新功能。由于线粒体与针对各种应激的心脏保护有关，MAVS 蛋白的发现表明，涉及心肌细胞内线粒体的抗病毒和心脏保护机制之间存在未识别的串扰。因此，在这里我们将剖析通过 MAVS 介导的心脏特异性先天抗病毒防御机制，并研究该机制在各种应激反应期间心脏保护中的含义。此外，我们尝试鉴定参与心脏特异性先天防御机制的新型 MAVS 相互作用分子。这将有助于我们了解心肌细胞抵御各种应激并长期维持体内平衡的分子机制的长期目标。阐明这些机制将确定可能有益于治疗多种心脏病的新治疗靶点，例如病毒介导的心肌病、扩张型心肌病、缺血性心脏病和中毒性心肌病。因此，我们提出以下具体目标： 1. 确定 MAVS 是否可以在心脏中诱导独立于 I 型 IFN 信号传导的抗病毒作用。这将通过检查 1) MAVS 和 2) I 型 IFN 受体的心脏特异性破坏对心肌细胞对 CVB3 感染的易感性的影响来完成。 3)通过将心脏特异性MAVS和I型IFN受体双敲除小鼠的表型与心脏特异性MAVS或I型IFN受体双敲除小鼠的表型进行比较，确定心肌细胞中MAVS依赖性但I型IFN独立的抗病毒防御机制的重要性I IFN 受体单基因敲除小鼠 CVB3 感染后。 2. 使用缺血再灌注 (I/R) 损伤作为氧化应激模型，确定 MAVS 对心脏功能是否具有生理或病理生理作用。这将通过检查 I/R 损伤下种系和心脏特异性 MAVS 敲除小鼠的表型来完成。 1) I/R损伤下MAVS与Bax以外的Bcl-2家族蛋白以及RIG-I和MDA-5以外的含CARD蛋白的相互作用；2) MAVS对NF-:B、IRF3的影响，I/R损伤下的IRF7、gp130、Akt和MAPK信号通路也将被确定。 3. 通过 1) 使用二维凝胶电泳和质谱的蛋白质组学方法，以及 2) 酵母双杂交筛选方法，鉴定将 MAVS 连接到下游先天防御机制的新型接头分子。公共健康相关性：该项目将有助于我们的长期目标，即了解心肌细胞在暴露于各种破坏性条件（例如病毒感染、缺血和药物毒性）时自我保护的分子机制。阐明这些机制将确定可能有益于治疗多种心脏病的新治疗靶点，例如病毒介导的心肌病、扩张型心肌病、缺血性心脏病和中毒性心肌病。