Arrhythmia Mechanisms Modulated by Intercalated Disc Extracellular Nanodomains

闰盘细胞外纳米结构域调节心律失常的机制

基本信息

批准号：
10668025
负责人：
Steven Poelzing
金额：
$ 64.66万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10668025
关键词：
Acute Adhesions Affect Animal Model Area Arrhythmia Biophysics Blood Substitutes Brugada syndrome Cardiac Cardiovascular Diseases Cell Adhesion Molecules Cell Communication Cells Collaborations Communication Connexin 43 Connexins Conscious Coupling Data Defibrillators Dependence Desmosomes Diagnostic Disease Early Diagnosis Edema Electrocardiogram Electrolytes Etiology Exhibits Functional disorder Gap Junctions Genes Heart Heart Diseases Human Injections Intercalated disc Investigation Ions Knock-out Laboratories Left Left ventricular structure Life Link Mannitol Maps Masks Measures Mechanics Methods Modeling Mus Mutation N-Cadherin Nature Optics Organism Osmosis Pathogenesis Pathology Pathway interactions Patient-Focused Outcomes Patients Peptides Phenotype Protein Isoforms Proteins Reporting Right ventricular structure Risk Reduction Secondary to Sodium Channel Stress Structural Protein Structure Sudden Death Syndrome Tail Testing Tissues Transmission Electron Microscopy Veins Ventricular Ventricular Arrhythmia Wild Type Mouse Work arrhythmogenic cardiomyopathy clinically relevant desmoplakin disease-causing mutation experimental study extracellular force sensor functional loss gene therapy in vivo induced pluripotent stem cell derived cardiomyocytes innovation intercellular communication interstitial loss of function loss of function mutation mouse model nano novel novel therapeutics oculodentodigital dysplasia patch clamp pharmacologic plakoglobin prevent protein expression response superresolution microscopy therapeutic target therapeutically effective voltage

项目摘要

PROJECT SUMMARY Loss-of-function mutations in the genes encoding the cardiac isoform of the voltage-gated sodium channel (Nav1.5) have been associated with the Brugada Syndrome (BrS), and loss-of-function of plakoglobin has been associated with Arrhythmogenic Cardiomyopathy (ACM). Both diseases are associated with inconsistent experimental findings, can be revealed by basic experimental differences, often affect the right ventricle, are associated with intercalated disc proteinopathies, and for both, there are few treatments to prevent arrhythmias. We have previously demonstrated that another loss-of-function in the intercalated disc protein connexin43 can be concealed by choice of experimental perfusate, potentially explaining why disease-related conduction slowing can be measured in some laboratories but can remain concealed in an intact organism with “normal” electrolyte composition. We also previously demonstrated that induced acute interstitial edema (AIE) is greater in the right relative to the left ventricle. Since AIE can unmask gap junction uncoupling, we hypothesize that AIE can unmask two other intercalated disc diseases: BrS and ACM. Finally, if AIE can unmask intercalated disc diseases, our data suggest that these diseases may be treatable by managing intercalated disc microdomain separation. In this project, we propose an innovative hypothesis that the concealed nature of BrS and ACM in intact tissue is mechanistically tied to a newly discovered form of cell-to-cell communication called ephaptic coupling. Upon successful completion of these aims, we will produce new methods to unmask these diseases in their pre- manifest stage, allowing for early detection. Further, the work will suggest important new therapies for two diseases with few effective therapeutic options and poor patient outcomes.

项目概要编码电压门控钠通道心脏亚型的基因发生功能丧失突变 (Nav1.5) 与布鲁格达综合征 (BrS) 有关，斑珠蛋白功能丧失已被证实与致心律失常性心肌病（ACM）相关，这两种疾病都与不一致相关。实验结果，可以通过基本实验差异揭示，通常影响右心室，是与闰盘蛋白病相关，对于这两种疾病，很少有治疗方法可以预防心律失常。我们之前已经证明，闰盘蛋白 connexin43 的另一种功能丧失可以被实验灌注液的选择所掩盖，可能解释为什么与疾病相关的传导减慢可以在一些实验室中测量，但可以隐藏在具有“正常”电解质的完整生物体中我们之前还证明，诱发的急性间质性水肿（AIE）在右侧更大。相对于左心室，由于 AIE 可以揭示间隙连接解偶联，我们勇敢地说 AIE 可以揭示。另外两种闰盘疾病：BrS 和 ACM 最后，如果 AIE 能够揭开闰盘疾病的面纱，我们的研究结果将是怎样的？数据表明，这些疾病可以通过管理闰盘微区分离来治疗。在这个项目中，我们提出了一个创新的假设，即完整组织中 BrS 和 ACM 的隐藏性质与一种新发现的细胞间通讯形式（称为“触觉耦合”）机械地联系在一起。成功完成这些目标后，我们将制定新的方法来揭露这些疾病的真相此外，这项工作将为两种疾病提出重要的新疗法。缺乏有效治疗选择且患者预后不佳的疾病。