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.

项目摘要编码电压门控钠通道心脏同工型的基因的功能丧失突变（NAV1.5）与Brugada综合征（BRS）有关，Plakoglobin的功能丧失一直存在与心律不齐的心肌病（ACM）有关。两种疾病都与不一致有关实验发现，可以通过基本的实验差异来揭示，通常会影响右心室，是与插入的椎间盘蛋白质病有关，并且对于两者，几乎没有治疗可预防心律不齐。我们以前已经证明，在插入的盘蛋白connexin43中的另一个功能丧失可以可以通过选择实验性灌注液隐藏，这有可能解释为什么与疾病相关的传导减速可以在某些实验室中测量，但可以在具有“正常”电解质的完整生物中隐藏作品。我们以前还证明诱导的急性间质水肿（AIE）在右边更大相对于左心室。由于AIE可以揭示缝隙连接的解偶联，因此我们假设AIE可以揭露另外两种插入的椎间盘疾病：BR和ACM。最后，如果AIE可以揭露插入的椎间盘疾病，我们数据表明，这些疾病可以通过管理插入的椎间盘微区分离来治疗。在这个项目中，我们提出了一个创新的假设，即完整组织中BR和ACM的隐藏性质机械地与新发现的细胞对细胞通信形式绑定，称为ephaptic耦合。之上这些目标成功完成，我们将制定新的方法，以揭露这些疾病的前明显的阶段，允许早期检测。此外，这项工作将为两者提供重要的新疗法几乎没有有效治疗选择和患者预后差的疾病。