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）：该项目的总体目的是确定新型线粒体蛋白，即心肌细胞中心肌细胞中线粒体抗病毒信号传导（MAV）的作用，当心肌细胞暴露于各种毁灭性疾病，例如病毒感染，急性压力过多，缺血性，缺血性和药物毒性。已经发现MAVS蛋白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。由于线粒体已与各种应力有关心脏保护作用，因此MAVS蛋白的发现表明抗病毒软件和心脏心肌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MAV介导的心脏特异性先天抗病毒防御机制，并检查各种应力反应中这种机制在心脏保护中的含义。此外，我们尝试鉴定出与心脏特异性先天防御机制相互作用的新型MAV相互作用的分子。这将有助于我们的长期目标，即理解心肌细胞免受各种压力并长期保持体内平衡的分子机制。阐明这些机制将确定可能有益于治疗多种心脏病的新型治疗靶标，例如病毒介导的心肌病，扩张的心肌病，缺血性心脏病和有毒的心肌病。因此，我们提出以下特定目的：1。确定MAV是否可以诱导与I型IFN信号无关的心脏中的抗病毒作用。这将通过检查1）MAV和2）I型IFN受体对心肌细胞对CVB3感染的敏感性的影响来完成。 3）心肌细胞中与MAVS依赖但I型IFN独立的抗病毒防御机制的重要性将通过将心脏特异性MAV和I型IFN受体双基因敲除小鼠与心脏特异性MAV或I型I IFN IFN受体单敲除单基因敲除单基因敲除小鼠的表型进行比较来确定。 2。确定MAV使用缺血 - 再灌注（I/R）损伤作为氧化应激的模型，在心脏功能上具有生理或病理生理作用。这将通过检查I/R损伤下的种系和心脏特异性MAV敲除小鼠的表型来完成。 1）MAV与BAX以外的Bcl-2家族蛋白以及I/R损伤下的RIG-I和MDA-5以外的其他含卡蛋白的相互作用以及2）MAV对NF-：B，IRF3，IRF7，IRF7，GP130，GP130，AKT和MAPK信号传导途径的影响也将确定。 3。确定新型的适配器分子通过1）使用二维凝胶电泳和质谱法连接到下游的先天防御机制，以及一种蛋白质组学方法，以及2）酵母两杂交筛选方法。公共卫生相关性：该项目将有助于我们的长期目标，即心脏肌细胞暴露于各种毁灭性疾病（例如病毒感染，缺血和药物毒性）时，心肌细胞捍卫自己的分子机制。阐明这些机制将确定可能有益于治疗多种心脏病的新型治疗靶标，例如病毒介导的心肌病，扩张的心肌病，缺血性心脏病和有毒的心肌病。