Extracellular Space as Modulator of Gap Junction-Conduction Velocity Relationship

细胞外空间作为间隙连接传导速度关系的调节器

• 批准号: 8037980
• 负责人: Steven Poelzing
• 金额: $ 37.5万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8037980
• 关键词: Accounting; Acute; Address; Affect; Albumins; Animal Experiments; Animal Model; Anisotropy; Anterior; Arrhythmia; Blood capillaries; Carbenoxolone; Cardiac; Cardiopulmonary Bypass; Cavia; Cell Size; Cellular Structures; Conflict (Psychology); Connexin 43; Connexins; Consensus; Coupling; Data; Dehydration; Dependence; Dependency; Disease; Dose; Down-Regulation; Dyes; Edema; Electrophysiology (science); Estimation Techniques; Extracellular Matrix; Extracellular Space; Failure; Fiber; Gap Junctions; Genetic Models; Glycyrrhetinic Acid; Goals; Heart; Heart Hypertrophy; Heart failure; Hypertension; Hypertrophy; Impairment; Intercalated disc; Intervention; Ischemia; Knockout Mice; Mannitol; Maps; Measurement; Measures; Mediating; Methodology; Modeling; Mus; Myocardial; Myocardial Ischemia; Optics; Perfusion; Phosphorylation; Play; Protocols documentation; Relative (related person); Reperfusion Therapy; Reporting; Research; Risk; Role; Simulate; Sodium Channel; Surface; Testing; Time; Tissues; Transgenic Organisms; United States; Ventricular; Ventricular Arrhythmia; Water; Weight; capillary; electric field; extracellular; interstitial; lymph flow; mathematical model; new therapeutic target; null mutation; pressure; response; sudden cardiac death; theories; therapeutic target; voltage

DESCRIPTION (provided by applicant): Sudden cardiac death during heart failure is a major concern in the United States and other Western Nations. The broad long term objectives of this study are to understand the time course and impact of heterogeneous gap junction and extracellular space remodeling during heart failure. It has been recently demonstrated that gap junction functional remodeling precedes conduction velocity changes by approximately two weeks.1 Since conduction slowing is implicated as a mechanism of sudden cardiac death, and the relationship between gap junctions and conduction velocity is a topic of significant controversy and debate, it is imperative to understand all the mechanisms that modify this relationship. Even more broadly speaking, the gap junction-conduction velocity (Gj-8) relationship is important for understanding sudden cardiac death in diseases such as ischemia, hypertrophy, and heart failure, because all three are associated with gap junctional remodeling and altered conduction. If the extracellular space significantly modulates the gap junction conduction velocity relationship as preliminarily demonstrated in this application, then modulating the cardiac extracellular space may be a previously untapped therapeutic target for heart failure. Our approach to address this hypothesis will bring together three state of the art methodologies and associated experts. 1. Dr. Steven Poelzing (PI), an expert on quantifying the Cx43-conduction velocity relationship, will be responsible for demonstrating that pharmacologically modulating ventricular ECS modulates Gj-8 relationship in pharmacologic and genetic models of Cx43 functional down-regulation. 2. Dr. Mohamed Salama (collaborator), an expert on morphometric analysis of cell structure and the extracellular matrix, will be responsible for determining how the ex-vivo interventions implemented by Dr. Poelzing changes cell size and the ECS. 3. Finally, Dr. James Keener, an expert of mathematically modeling cardiac conduction will develop a model of cardiac conduction that includes electric-field coupling in addition to gap junctional coupling. This model will include all the data collected from Drs. Poelzing, and Salama. The mathematical model will be validated against all interventions proposed in the animal experiments. PUBLIC HEALTH RELEVANCE: Ventricular arrhythmias account for 80% of over 450,000 cases of sudden cardiac death that occur in the U.S. each year. While there is an established association between aberrant conduction and arrhythmias, the mechanisms of conduction failure in diseases such as heart failure and ischemia remain unknown. Interestingly, two common findings in heart failure and ischemia are an increased extracellular volume (i.e. edema) and impairment of intercellular coupling. The role of intercellular coupling is well researched, but controversial, and the role of the extracellular volume has been largely ignored until recently. The purpose of this proposal is to demonstrate that the extracellular space is an important determinant of risk for sudden cardiac death since it modulates the relationship between intercellular coupling and cardiac conduction. Modulating the extracellular space represents a novel therapeutic target for heart failure and sudden cardiac death.

描述（由申请人提供）：心力衰竭期间的心源性猝死是美国和其他西方国家的一个主要问题。这项研究的广泛长期目标是了解心力衰竭期间异质间隙连接和细胞外空间重塑的时间过程和影响。最近已经证明，间隙连接功能重塑先于传导速度变化大约两周。1由于传导减慢被认为是心源性猝死的一种机制，而间隙连接和传导速度之间的关系是一个备受争议和争论的话题，因此必须了解改变这种关系的所有机制。更广泛地说，间隙连接-传导速度 (Gj-8) 关系对于理解缺血、肥厚和心力衰竭等疾病中的心源性猝死非常重要，因为这三者都与间隙连接重塑和传导改变有关。 如果细胞外空间显着调节间隙连接传导速度关系，如本申请中初步证明的，那么调节心脏细胞外空间可能是先前未开发的心力衰竭治疗目标。 我们解决这一假设的方法将汇集三种最先进的方法和相关专家。 1. Steven Poelzing 博士 (PI) 是一位量化 Cx43-传导速度关系的专家，他将负责证明药物调节心室 ECS 在 Cx43 功能下调的药理学和遗传模型中调节 Gj-8 关系。 2. Mohamed Salama 博士（合作者）是细胞结构和细胞外基质形态分析专家，他将负责确定 Poelzing 博士实施的离体干预措施如何改变细胞大小和 ECS。 3. 最后，心脏传导数学建模专家 James Keener 博士将开发一种心脏传导模型，除了间隙连接耦合之外，还包括电场耦合。该模型将包括从 Drs 收集的所有数据。波尔津和萨拉马。数学模型将根据动物实验中提出的所有干预措施进行验证。 公共卫生相关性：美国每年发生超过 45 万例心源性猝死，其中 80% 是由室性心律失常引起的。虽然异常传导和心律失常之间已确定存在关联，但心力衰竭和缺血等疾病中传导衰竭的机制仍不清楚。有趣的是，心力衰竭和缺血的两个常见发现是细胞外体积增加（即水肿）和细胞间耦合受损。细胞间耦合的作用已得到充分研究，但存在争议，并且直到最近，细胞外体积的作用在很大程度上被忽视。该提案的目的是证明细胞外空间是心源性猝死风险的重要决定因素，因为它调节细胞间耦合和心脏传导之间的关系。调节细胞外空间代表了心力衰竭和心源性猝死的新治疗靶点。