Targeting Vascular Leak and Intercalated Disk Nanodomains to Prevent Atrial Fibrillation

靶向血管渗漏和闰盘纳米结构域以预防心房颤动

• 批准号: 10449096
• 负责人: Rengasayee Veeraraghavan
• 金额: $ 43.56万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10449096
• 关键词: 3-Dimensional; AF2; Acute; Address; Adherens Junction; Adhesions; Adhesives; Affect; Animals; Anti-Arrhythmia Agents; Arrhythmia; Atrial Fibrillation; Atrial Function; Biochemical; Blood Vessels; Calsequestrin; Cardiac; Cardiac Edema; Cardiovascular Diseases; Connexin 43; Data; Defect; Dependence; Desmosomes; Dose; Drug Targeting; Edema; Electron Microscopy; Electrophysiology (science); Endothelial Growth Factors Receptor; Gap Junctions; Heart; Heart Atrium; Human; IL2 gene; Image; Impairment; Inflammation; Inflammatory; Intercalated disc; KDR gene; Knock-out; Knockout Mice; Link; Microscopy; Modeling; Molecular; Mus; Muscle Cells; Myocardial; N-Cadherin; Neonatal; Patch-Clamp Techniques; Pathology; Patients; Peptides; Plant Roots; Population; Precipitation; Resolution; Risk; Role; Serum; Site; Sodium Channel; Structure; Structure-Activity Relationship; Swelling; Testing; Tissues; Transgenic Mice; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Wild Type Mouse; Work; clinically relevant; cytokine; desmoglein; efficacy testing; experimental study; in vivo; in vivo Model; inhibitor; innovation; monolayer; nanoscale; novel; novel therapeutics; patch clamp; peptidomimetics; preservation; prevent; single molecule; stem; stroke risk; thrombogenesis; tool; vascular contributions

ABSTRACT Inflammation and vascular leak are common findings across several pathologies associated with arrhythmias. These include atrial fibrillation (AF), which affects up to 3% of the US population. AF progressively worsens, and increases risk of stroke and cardiovascular disease. Thus, we urgently need novel, mechanistically-driven therapies for AF. Vascular leak in AF patients results from elevated serum levels of inflammatory cytokines such as vascular endothelial growth factor (VEGF). While the thrombogenic impact of vascular leak in AF is widely recognized, its role in arrhythmogenesis remains unclear. One possible link between vascular leak and arrhythmia may be myocardial edema. Recent work by the PI demonstrated that edema disrupts sodium channel (NaV1.5) –rich nanodomains within the intercalated disk (ID), slowing cardiac impulse propagation, and prompting arrhythmias. In preliminary studies, VEGF (at levels found in the serum of AF patients) elevated AF inducibility ex vivo and in vivo mouse experiments within 30 minutes. Therefore, we hypothesize that cytokine-induced vascular leak promotes cardiac edema, and contributes to atrial arrhythmias by disrupting NaV1.5-rich ID nanodomains. In this venture, we will employ cutting edge tools including super-resolution microscopy, 3D electron microscopy, and smart patch clamp to investigate the structural and functional impact of vascular leak on the structure and function of atrial IDs. Furthermore, we will utilize an innovative strategy peptide mimetics of adhesion domains will be used to selectively modulate the structure of different ID nanodomains. Aim 1 will use these peptides to investigate how different ID nanodomains contribute to atrial conduction, and probe fundamental mechanisms underlying these structure-function relationships. In new preliminary data, we demonstrate that VEGF- induced vascular leak induces swelling of ID nanodomains and translocation of NaV1.5 from these sites within 30 minutes. Aim 2 will investigate the acute structural and functional impacts of VEGF- induced vascular leak. Aim 3 will use ex vivo and in vivo models to test the efficacy of preserving the vascular barrier and/or ID nanodomains in preventing AF.

抽象的 炎症和血管泄漏是几种相关病理的常见发现 与心律不齐。其中包括心房颤动（AF），影响多达3％的美国人口。 AF逐渐恶化，并增加了中风和心血管疾病的风险。那，我们 迫切需要用于AF的新型，机械驱动的疗法。 AF患者的血管泄漏结果 从血清升高的炎性细胞因子（例如血管内皮生长因子）的水平升高 （VEGF）。尽管广泛认识到血管泄漏对AF的血栓形成影响，但其在 心律不齐仍然不清楚。血管泄漏和心律不齐之间的一个可能联系可能 成为心肌水肿。 PI的最新工作表明水肿破坏了钠通道 （NAV1.5） - 插入式磁盘（ID）内的富含纳米域（ID），心脏脉冲放缓 繁殖并促使心律不齐。在初步研究中，VEGF（在 AF患者的血清升高AF诱导性离体和体内小鼠实验30之内 分钟。因此，我们假设细胞因子诱导的血管泄漏会促进心脏 水肿，并通过破坏NAV1.5富丽的ID纳米域来促进心律不齐。在 这项合资企业，我们将采用尖端工具，包括超分辨率显微镜，3D电子 显微镜和智能贴片夹以研究血管的结构和功能影响 房间ID的结构和功能泄漏。此外，我们将利用一种创新的策略 粘附结构域的肽模拟物将用于选择性调节结构 不同的ID纳米域。 AIM 1将使用这些PETIDE来研究不同的ID 纳米域有助于心房传导和探测基本机制 这些结构功能关系。在新的初步数据中，我们证明了VEGF- 诱导的血管泄漏可引起ID纳米域的肿胀和NAV1.5的易位 站点在30分钟内。 AIM 2将研究VEGF-的急性结构和功能影响 诱导的血管泄漏。 AIM 3将使用离体和体内模型测试保存效率 防止AF的血管屏障和/或ID纳米域。