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Novel Signaling Mechanisms and Molecular Targets in the Stressed Myocardium

应激心肌中的新型信号传导机制和分子靶点

基本信息

批准号：
8476260
负责人：
Peipei Ping
金额：
$ 70.91万
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：
2010-07-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8476260
关键词：
26S proteasome Ablation Address Area Attenuated Biology Boxing Cardiac Cardiovascular system Cells Complex Coronary Occlusions Data Defect Degradation Pathway Development Disease Disease model Down-Regulation Ensure Event Functional disorder Genetic Genetic Models Goals Heart Heart Diseases Heart Hypertrophy Heart failure Homeostasis Housing Image Injury Investigation Joints Knock-in Mouse Knowledge Laboratories LacZ Genes Lesion Mediating Methods Mitochondria Mitochondrial Proteins Modeling Modification Molecular Molecular Target Mus Myocardial Myocardium Nature Organism Oxidative Stress Pathogenesis Permeability Post-Translational Protein Processing Protein phosphatase Proteins Proteomics Quality Control Reactive Oxygen Species Reagent Regulation Research Research Infrastructure Research Personnel Resolution Resources Role Signal Transduction Stress Superoxides System Techniques Technology Testing Tetanus Helper Peptide Therapeutic clinically relevant constriction design experience injured innovation insight multicatalytic endopeptidase complex novel novel therapeutics pressure prevent protein degradation public health relevance research study tool

项目摘要

DESCRIPTION (provided by applicant): Oxidative stress has been increasingly recognized as a common feature among different forms of heart disease. Elevated reactive oxygen species (ROS) has been shown as a convergent signaling messenger leading to failing heart either of ischemic or non-ischemic origin. Despite significant progress in many areas of ROS related investigations, two fundamental issues remain unresolved and will constitute the center of this proposed investigation. The first question is who are the regulators of ROS in the diseased myocardium? The second question is what are the molecular targets of ROS and how do ROS-induced molecular modifications result in cardiac dysfunction? This application is inspired by our exciting data identifying PP2Cm as a novel regulator of ROS; and by the intriguing preliminary evidence that the cardiac proteasome complexes are a new class of molecular targets for ROS. Accordingly, the proposed investigation will address a novel aspect of ROS signaling: its modulation by PP2Cm, and it will embark on a largely unexplored area of research: the functional consequences of ROS elevation--its impact on the proteasome systems and their substrates. The application will determine the emerging role of PP2Cm in ROS biology; it will establish proteasome subunits as a new set of molecular targets for the elevated ROS; and it will systematically characterize perturbed protein degradation pathways in the normal and stressed myocardium. Furthermore, the application will identify potential therapeutic windows whereby disrupted protein quality control may be rescued. To accomplish our goals, two related models of cardiac stress--pressure overload by transverse-aortic constriction (TAC) and myocardial ischemic injury (I/R)-are employed. Three specific aims are proposed: Aim 1 will elucidate mechanisms underlying PP2Cm mediated protection of the heart; it will determine its role in governing ROS regulation and examine the impact of genetic perturbations of PP2Cm in TAC and I/R using the newly established PP2Cm genetic models in-house (the null/LacZ knock-in KO and the cardiac conditional inducible Tet-Off). Aim 2 will establish roles of the 20S and 26S proteasomes in the two stress models with respect to proteasome complex assembly, function, and degradation capacity; it will decipher molecular events underlying ROS damaged 20S and 26S proteasomes. It will apply a targeted proteomic approach to delineate the molecular modification of proteasome subunits; and it will define the functional significance of such modifications. Aim 3 will define functional consequences of ROS-injured 20S and 26S proteasomes in the two pathological models; it will characterize the substrate repertoire of 20S and 26S proteasomes in the normal and stressed myocardium. Our research plan is supported by "a technology tool box" combining established methods and innovative approaches assembled by the investigator team. It encompasses genetic models, proteasome biology, ROS biology, disease models, quantitative proteomics, and high-resolution imaging. Collectively, the proposed studies will conclusively characterize PP2Cm regulation of ROS in the stress myocardium; it will establish proteasome subunits as novel targets of ROS; and it will provide mechanistic insights into protein homeostasis in the two stress models.

描述（由申请人提供）：