Extracellular Space as Modulator of Gap Junction-Conduction Velocity Relationship

摘要 心力衰竭时的心源性猝死是美国和其他西方国家的主要担忧 国家。这项研究的广泛长期目标是了解时间进程和影响 心力衰竭时的异质性缝隙连接和细胞外间隙重构。它是最近发生的 证明缝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， 缝隙连接和传导速度之间的关系是一个有重大争议和争论的话题，它是 必须了解修改这种关系的所有机制。更广泛地说， 缝隙连接-传导速度(GJ-？)关系对了解心源性猝死有重要意义 疾病，如缺血、肥大和心力衰竭，因为这三种疾病都与缝隙连接有关 重塑和传导改变。 如果细胞外空间显著调节缝隙连接传导速度关系为 在这一应用中初步证明，那么调节心脏细胞外间隙可能是一种 之前未开发的心力衰竭治疗靶点。 我们解决这一假设的方法将结合三种最先进的方法和 联合专家。 1.量化Cx43-传导速度关系的专家Steven Poelzing(PI)博士将 负责证明药物调节的心室内皮细胞调节GJ？ Cx43功能下调的药理学模型与遗传学模型的关系 2.Mohamed Salama博士(合作者)，细胞结构形态计量分析专家 细胞外基质，将负责确定体外干预如何实施博士。 Poelze改变了细胞大小和ECS。 3.最后，心脏传导数学建模专家詹姆斯·基纳博士将开发一个模型 心脏传导，除了缝隙连接耦合外还包括电场耦合。这款车型将 包括从波尔津博士和萨拉马博士那里收集的所有数据。将对数学模型进行验证 反对动物实验中提出的所有干预措施。

ABSTRACT 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-¿) 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-¿ 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.