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Mitochondrial pathways in NO induced cardioprotection

NO 诱导的心脏保护中的线粒体途径

基本信息

批准号：
7848018
负责人：
Hua Linda Cai
金额：
$ 61.51万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7848018
关键词：
Address Behavior Biological Preservation Biology Calcium Cardiac Cardiac Myocytes Cells Computer Simulation Data Disease Dominant-Negative Mutation Elements Ensure Event Genetic Models Goals Homeostasis Housing Injury Investigation Joints Knock-out Knockout Mice Laboratories Lead Mediating Membrane Potentials Methods Mitochondria Modeling Molecular Molecular Target Mus Muscle Cells Myocardial Nature Nitric Oxide Nitric Oxide Donors Organism Pathogenesis Pathway interactions Patient Care Phase Phenotype Phosphotransferases Play Population Post-Translational Protein Processing Production Property Proteins Proteome Proteomics Reactive Oxygen Species Reagent Regulation Reperfusion Injury Research Research Infrastructure Resources Role Signal Transduction Signaling Molecule Simulate Specific qualifier value Systems Integration Techniques Testing Translating Work abstracting base design feeding innovation insight mathematical model mitochondrial membrane novel public health relevance research study reuptake src-Family Kinases uptake

项目摘要

DESCRIPTION (provided by applicant): Investigations in the past decades have significantly advanced our understanding of signaling mechanisms underlying the protection and pathogenesis of myocardial ischemic injury. It is increasingly recognized that preservation of mitochondrial function plays a pivotal role in cardioprotection against ischemia reperfusion injury (I/R). However, it remains virtually unknown as to who the molecular targets of cardioprotection are in the mitochondria; what specific molecular events led to the protection of mitochondria; and whether there is a systems integration of cardioprotective signaling at the mitochondria to support the manifestation of a protected phenotype. Using a murine model of nitric oxide (NO) induced late phase of cardioprotection, we elect to examine the plausible intrinsic signaling properties of mitochondria using a novel experimental strategy enabling a parallel examination of mitochondrial signaling, mitochondrial proteomes, and mitochondrial behavior by computational modeling. The proposed studies are based upon preliminary evidence by others and our own demonstrating that activation of PKC?-Src module occurs in the NO donor treated mice and that both are localized to mitochondrial membranes. In this proposal we will test the innovative hypothesis that the PKC?-Src module interacts with the brief mPTP openings to protect cardiomyocytes from Ca++ overload induced jury. The working hypothesis is that NO activates PKC?-Src module, leading to brief mPTP openings which results in transients Ca++ releases and reactive oxygen species (ROS) bursts, and consequently inactivates Ca++ reuptake and further activates PKC?-Src to form a feed- forward loop. When the homeostasis is interrupted (e.g., calcium overload or elevated ROS), brief mPTP openings transits into irreversible, long-lasting mPTP openings, which instead induce cardiac injury. In this application we propose to delineate the functional effects of brief openings of mPTP on Ca++ handling and ROS production; and to elucidate mPTP regulation by the mitochondrial PKC?-Src module in the setting of NO-induced late phase of cardioprotection (Aim 1). In the specific Aim 2 we will conclusively establish the activation of a PKC?-Src signaling module in the mitochondria as a mandatory signaling element of NO-induced cardioprotection against myocardial ischemic injury. At last we will systematically define the molecular targets of mitochondrial Src-kinase in NO- induced late phase of cardioprotection (Aim 3). The proposed studies will advance our understanding of cardiac biology by providing novel mechanistic insights into how interactions of brief mPTP openings with mitochondrial PKC?-Src module can be beneficial in mediating NO-induced late phase of cardioprotection. (End of Abstract)

描述（由申请人提供）：