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

基本信息

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
项目类别：
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

项目摘要

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）：心力衰竭期间心脏猝死是美国和其他西方国家的主要问题。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的变化大约两个星期。1自从传导放缓牵涉到心脏突然死亡的机制，而间隙连接速度与传导速度之间的关系是一个重大争议和辩论的主题，这是一个重大的争议和辩论的主题，可以理解所有机制来修改这种关系。更广泛地说，间隙连接导导速度（GJ-8）关系对于理解诸如缺血，肥大和心力衰竭的疾病中的心脏死亡至关重要，因为这三个疾病都与间隙连接重塑并改变了传导。如果细胞外空间显着调节了本应用初步证明的间隙连接速度关系，那么调节心脏外空间可能是先前未开发的心脏衰竭治疗靶标。我们解决这一假设的方法将汇集三种艺术方法和相关专家。 1。量化CX43导能速度关系的专家Steven Poelzing博士（PI）将负责证明，在CX43功能下调的药理学调节心室ECS的药理学调节室中的GJ-8关系。 2。穆罕默德·萨拉马（Mohamed Salama）博士（合作者）是细胞结构和细胞外矩阵的形态计量学分析专家，将负责确定Poelzing博士在Poelzing博士实施的前体内干预措施如何改变细胞大小和ECS。 3.最后，数学建模心脏传导专家詹姆斯·基纳（James Keener）博士将开发一种心脏传导模型，除间隙连接耦合外，还包括电场耦合。该模型将包括从DRS收集的所有数据。 Poelzing和Salama。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：每年在美国发生的450,000例猝死的心脏心律失常中，有80％的心律失常。尽管异常传导与心律不齐之间存在建立的关联，但心力衰竭和缺血等疾病中传导失败的机制仍然未知。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）和细胞间耦合的损害。细胞间耦合的作用进行了充分的研究，但有争议，细胞外体积的作用在很大程度上被忽略了。该提案的目的是证明细胞外空间是心脏猝死风险的重要决定因素，因为它调节了细胞间耦合与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脏猝死的新型治疗靶点。