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.
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.
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|Yajima, Toshitaka; Murofushi, Yoshiteru; Zhou, Hanbing et al. (2011) Absence of SOCS3 in the cardiomyocyte increases mortality in a gp130-dependent manner accompanied by contractile dysfunction and ventricular arrhythmias. Circulation 124:2690-701|
|Yajima, Toshitaka (2011) Viral myocarditis: potential defense mechanisms within the cardiomyocyte against virus infection. Future Microbiol 6:551-66|