Extracellular Space as Modulator of Gap Junction-Conduction Velocity Relationship

摘要 心力衰竭期间的心源性猝死是美国和其他西方国家的主要关注点。 Nations.本研究的广泛长期目标是了解 异质性缝隙连接与细胞外间隙重构最近已经 结果表明，缝隙连接功能重塑先于传导速度变化约 由于传导减慢是心脏性猝死的一种机制， 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， 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-<$）关系对于理解心脏性猝死很重要， 心肌缺血、心肌肥厚和心力衰竭等疾病，因为这三种疾病都与缝隙连接有关。 重塑和传导改变 如果细胞外间隙显著调节差距连接传导速度关系， 在本申请中初步证明，那么调节心脏细胞外空间可能是一种 以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汇集三种最先进的方法， 相关专家。 1. Steven Poelzing博士（PI）是量化Cx43-传导速度关系的专家， 负责证明调节心室ECS调节Gj-β的 Cx43功能下调的药理学和遗传学模型之间的关系。 2. Mohamed Salama博士（合作者），细胞结构形态测定分析专家， 细胞外基质，将负责确定如何离体干预实施博士。 Poelzing改变细胞大小和ECS。 3.最后，詹姆斯·基纳博士，一位数学建模心脏传导的专家，将开发一个模型， 除了间隙连接耦合之外还包括电场耦合的心脏传导。这种模式的 包括从波尔青博士和萨拉马博士那里收集的所有数据。数学模型将得到验证 与动物实验中提出的所有干预措施相反。

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.