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Targeting Pannexin 1 as a Novel Mechanism for Arrhythmia and Fibrosis in Duchenne Cardiomyopathy

靶向 Pannexin 1 作为杜氏心肌病心律失常和纤维化的新机制

基本信息

批准号：
10326854
负责人：
Frank J Raucci
金额：
$ 14.86万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-07 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10326854
关键词：
18 year old Abbreviations Ablation Age Apoptosis Apoptotic Arrhythmia Biology Ca(2+)-Transporting ATPase Calcium Cardiac Cardiac Electrophysiologic Techniques Cardiac Myocytes Cardiac development Cardiovascular Diseases Cause of Death Cell Nucleus Cells Cessation of life Childhood Coculture Techniques Complex Culture Techniques Data Defect Development Diagnosis Dilated Cardiomyopathy Disease Duchenne cardiomyopathy Duchenne muscular dystrophy Dystrophin Fibroblasts Fibrosis Foundations Functional disorder Funding Gene Expression Generations Genes Genetic Goals Heart Diseases Heart failure Histopathology Home Human Hypoxia Inflammasome Inflammation Inflammatory Investigation Ions Isoproterenol Knock-out Lead Link Measures Mediator of activation protein Membrane Mentorship Modality Modeling Molecular Morbidity - disease rate Muscle Cells Muscle Weakness Muscular Dystrophies Myocardial dysfunction Pathologic Pathway interactions Patients Persons Pharmacology Phenotype Physicians Play Population Primary Myocardial Diseases Process Proteins Proton-Translocating ATPases Purinoceptor Regulation Research Research Personnel Risk Role Ryanodine Receptor Calcium Release Channel Sarcoplasmic Reticulum Scientist Signal Pathway Signal Transduction Skeletal Muscle Stretching Structure Supportive care Symptoms Testing Time Training Programs Transgenic Mice Transgenic Organisms Ventricular Ventricular Arrhythmia base boys cardioprotection cardiovascular health cell motility cell type coronary fibrosis curative treatments experimental study extracellular genetic approach heart function heart rhythm improved in vivo induced pluripotent stem cell marenostrin migration mortality mouse model new therapeutic target novel preservation prevent programs recruit skills small molecule targeted treatment translational study ventilation

项目摘要

PROJECT SUMMARY Cardiovascular disease is the primary cause of death for patients with Duchenne muscular dystrophy (DMD). Arrhythmia and cardiac fibrosis leading to dilated cardiomyopathy are the primary mechanisms of cardiac mortality. Pannexins (Pxs), which are large conductance ion and small molecule channels, have been implicated in other fibroproliferative diseases and are thought to be arrhythmogenic in other model of cardiac disease. Loss of dystrophin, the primary defect in DMD, leads to elevated intracellular calcium (Ca2+) which is also a primary effector of Pxs. The goal of this project is to investigate the mechanisms by which Px1 modulates the development of cardiac fibrosis and arrhythmogenesis in models of DMD cardiomyopathy. Our preliminary data demonstrate a novel role for Px1 in the development of cardiac fibrosis and inducible arrhythmia seen in the D2-mdx model of DMD. Genetic ablation of Px1 in the D2-mdx model (mdxPx1-/-) rescues the cardiac phenotype, including normalization of cardiac fibrosis.as assessed by histopathology and significant reduction in isoproterenol-induced ventricular ectopy. Based on these data, we hypothesize that pathologically elevated intracellular Ca2+, a hallmark of this disease, leads to Px1 activation and results in signaling cascades that activate apoptotic, oxidative, and inflammatory pathways that ultimately lead to fibroblast activation and the development of cardiac fibrosis. We also hypothesize that Px1 channels represent an independent mechanism for ventricular arrhythmia via generation of delayed after-depolarizations (DADs). We with test these hypotheses using the 3 specific aims outlined in this proposal. In Aim 1, we will use transgenic mice with global Px1 deletion in addition to pharmacological Px inhibition to determine if Px1 activation results in triggered arrhythmia. In Aim 2, we will identify the mechanism by which Px1 contributes to cardiac fibrosis in DMD cardiomyopathy using pharmacological and genetic strategies. As Pxs are expressed in both cardiomyocytes and cardiac fibroblasts, Aim 3 will test if fibroblast migration is dependent on Px1 activation in cardiomyocytes and/or fibroblasts using co-culture techniques for human induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) and cardiac fibroblasts. The completion of these studies will help to improve our understanding of the mechanisms of cardiovascular disease in DMD and will provide the basis for further investigation of a novel therapeutic target that has the potential to delay or prevent cardiac mortality in DMD patients. Additionally, this proposal will allow a promising young physician scientist to gain important skill in basic and translational studies in cardiac electrophysiology, cell signaling, and inflammation/fibrosis biology under the expert guidance of a highly accomplished and dedicated mentorship committee. These new skills will provide the foundation for a successful transition from junior investigator to an independently-funded academic physician scientist.

项目总结