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: 8207841
• 负责人: Steven Poelzing
• 金额: $ 37.38万
• 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 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8207841
• 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

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.

抽象的 心力衰竭期间心脏猝死是美国和其他西方的主要问题 国家。这项研究的广泛长期目标是了解时间课程和影响 心力衰竭期间的异质间隙连接和细胞外空间重塑。最近已经 证明间隙连接函数重塑的前面传导速度的变化大约变化 两个星期。1自传导放缓牵涉到心脏猝死的机制，并且 间隙连接与传导速度之间的关系是引起重大争议和辩论的话题，这是 必须了解修改这种关系的所有机制。更广泛地说， 间隙连接速度速度（GJ- - ）关系对于理解心脏突然死亡很重要 缺血，肥大和心力衰竭等疾病，因为这三个疾病都与间隙连接 重塑和改变传导。 如果细胞外空间显着调节间隙连接传导速度关系 在此应用中最初证明了，然后调节心脏外空间可能是一个 以前未开发的心力衰竭治疗靶标。 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。量化CX43降低速度关系的专家Steven Poelzing博士（PI）将是 负责证明药理调节心室ECS会调节GJ-® CX43功能下调的药理学和遗传模型的关系。 2。穆罕默德·萨拉马（Mohamed Salama） 细胞外矩阵将负责确定博士博士的前体内干预措施是如何实施的。 po以改变细胞的大小和EC。 3。最后，数学建模心脏传导专家詹姆斯·基纳（James Keener）博士将开发一个模型 心脏传导除了间隙连接耦合外，还包括电场耦合。这个模型将 包括从DRS收集的所有数据。 Poelzing和Salama。数学模型将得到验证 反对动物实验中提出的所有干预措施。