Connexons in Cardiovascular Cell Communication

说明(申请人提供)：房颤是人类最常见的心律失常，发病率高，死亡率高。缝隙连接通道可能在心房颤动的稳定和维持中发挥重要作用，因为心房颤动与心房肌细胞之间连接的重塑和电传导改变有关。这些通道(由连接蛋白亚基Cx组成)为离子和小分子在细胞间的直接传递提供了一条途径，促进了心脏电传导和心血管细胞对细胞内信号的反应的协调。两种主要的连接蛋白(CX40和CX43)在心房表达。多项具有刺激性的研究表明，CX40的改变(包括水平降低、分布不均和突变)参与了房颤的发病。我们提出了一系列实验：(1)检验房颤患者的心房组织中存在Cx40单独或相对Cx43改变的假设，以及(2)使用表达系统来测试这些改变如何影响细胞间通讯。拟议的实验结果将阐明缝隙连接在心律失常中的作用。他们还将阐明缝隙连接介导的细胞间通讯的基本细胞生物学和生理学。 与公共卫生相关：心脏的正常功能依赖于细胞之间的电流传递，并由称为缝隙连接的结构中包含的细胞间通道促进。电传导障碍会导致异常心律，如房颤。我们的研究将阐明亚单位缝隙连接蛋白的异常是如何导致房颤等心律失常的。

DESCRIPTION (provided by applicant): Atrial fibrillation is the most common arrhythmia in man and confers a significant morbidity and increased risk of mortality. Gap junction channels are likely to play significant roles in the stabilization and maintenance of atrial fibrillation, since atrial fibrillation is associated with remodeling of connections between atrial myocytes and altered electrical conduction. These channels (made of connexin subunits, CX) provide a pathway for direct intercellular passage of ions and small molecules facilitating cardiac electrical conduction and coordination of the responses of cardiovascular cells to intracellular signals. Two major connexins (CX40 and CX43) are expressed in the atrium. A variety of provocative studies suggest that alterations of CX40 (including reduced levels, heterogeneity of distribution, and mutations) contribute to the pathogenesis of atrial fibrillation. A series of experiments are proposed: (1) to test the hypothesis that alterations of CX40 alone or relative to CX43 are present in atrial tissue from patients with atrial fibrillation, and (2) to use expression systems to test how these alterations can affect intercellular communication. The results of the proposed experiments will clarify the role of gap junctions in cardiac arrhythmias. They will also elucidate the basic cellular biology and physiology of gap junction-mediated intercellular communication. PUBLIC HEALTH RELEVANCE: The normal functioning of the heart depends on passage of electrical current between cells and is facilitated by intercellular channels contained within structures known as gap junctions. Disturbances of electrical conduction lead to abnormal heart rhythms such as atrial fibrillation. Our studies will clarify how abnormalities of the subunit gap junction proteins lead to arrhythmias such as atrial fibrillation.