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

基本信息

批准号：
10171612
负责人：
Rengasayee Veeraraghavan
金额：
$ 44.06万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10171612
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/antagonist innovation monolayer nanoscale novel novel therapeutics patch clamp peptidomimetics preservation prevent single molecule stem stroke risk thrombogenesis tool vascular contributions

项目摘要

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.

抽象的炎症和血管渗漏是多种相关病理学的常见发现其中包括心房颤动 (AF)，影响高达 3% 的美国人口。房颤逐渐恶化，并增加中风和心血管疾病的风险。迫切需要针对 AF 患者血管渗漏的新型机械驱动疗法。来自炎症细胞因子（例如血管内皮生长因子）血清水平升高 (VEGF) 虽然血管渗漏对 AF 的血栓形成影响已得到广泛认可，但其作用心律失常的发生机制尚不清楚。血管渗漏与心律失常之间可能存在一种联系。 PI 最近的研究表明，水肿会破坏钠离子通道。 (NaV1.5) – 闰盘 (ID) 内富含纳米域，减缓心脏冲动在初步研究中，VEGF（在体内发现的水平）。 AF 患者的血清）在 30 年内体外和体内小鼠实验中 AF 诱导能力升高因此，我们追寻细胞因子诱导的血管渗漏促进心脏。水肿，并通过破坏富含 NaV1.5 的 ID 纳米结构域而导致房性心律失常。在这个项目中，我们将采用最先进的工具，包括超分辨率显微镜、3D 电子显微镜和智能膜片钳研究血管的结构和功能影响此外，我们将利用创新策略。粘附结构域的肽模拟物将用于选择性调节目标 1 将使用这些肽来研究不同 ID 的差异。纳米域有助于心房传导并探索基本机制在新的初步数据中，我们证明了 VEGF- 这些结构-功能关系。诱导的血管渗漏引起 ID 纳米域的膨胀和 NaV1.5 的易位目标 2 将在 30 分钟内研究 VEGF- 的急性结构和功能影响。 Aim 3将使用离体和体内模型来测试保存的效果。血管屏障和/或 ID 纳米域在预防 AF 中的作用。