Adhesion Molecules of the Intercalated Disc in Cardiomyopathy

心肌病闰盘的粘附分子

• 批准号: 7905098
• 负责人: Kirk U Knowlton
• 金额: $ 31.07万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7905098
• 关键词: Actins; Adherens Junction; Adhesives; Adult; Affect; Alleles; Arrhythmia; Arrhythmogenic Right Ventricular Dysplasia; Attention; Binding; Binding Proteins; Breeding; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular system; Cell Adhesion Molecules; Cell membrane; Cell-Cell Adhesion; Cell-Matrix Junction; Cells; Complex; Connexin 43; Coupling; Coxsackie Viruses; Cytoskeleton; Data; Desmosomes; Development; Dilated Cardiomyopathy; Dysphasia; Embryo; Embryonic Heart; Epithelial Cells; Extracellular Matrix; Fascia; Fascia adherens; Gap Junctions; Genetic Recombination; Growth; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Human; Hypertrophy; Immunoglobulin Domain; Inherited; Integral Membrane Protein; Intercalated disc; Intercellular Junctions; Investigation; Knock-out; Knockout Mice; Laboratories; Lead; Learning; Link; Location; Mechanics; Mediating; Membrane; Microfilaments; Molecular; Mus; Muscle Cells; Myocardium; Myosin Heavy Chains; N-Cadherin; Pathogenesis; Pathway interactions; Pattern; Physiologic intraventricular pressure; Property; Protein Array; Protein Binding; Proteins; Reporting; Role; Sarcolemma; Side; Structure; Technology; Text; Tight Junctions; Time; Tissues; Transgenic Mice; Transgenic Organisms; Troponin I; Ventricular; Ventricular Function; adenovirus receptor; base; cardiogenesis; cell type; mortality; normal aging; numb protein; pressure; programs; promoter; protein structure; receptor binding; receptor expression; transgene expression; ventricular hypertrophy

ntercalated discs (ICD) are the major cardiac cell-cell adhesion structures, which connect muscle cells to one another. They consist of an array of proteins, which are categorized into three major junctional complexes, fascia adherens junctions, desmosomes, and gap junctions, and are essential for maintaining mechanical and electrical coupling between neighboring muscle cells/Abnormalities in the intercalated disc have been linked to hereditary forms of dilated cardiomyopathy such as arrhythmogenic right ventricular dysphasia/ cardiomyopathy (ARVD/C). Also abnormalities in the intercalated disc has been reported in the setting of cardiomyopathy. The coxsackievirus adenovirus receptor (CAR) is localized primarily at the ntercalated disc in the adult heart. While we and others have shown that CAR expression is required for normal cardiovascular development, relatively little is known of the functional significance of CAR and its associated molecules in the adult heart and in formation of the normal intercalated disc. The underlying hypothesis for this project is that CAR and ZO-1 expression are required for normal cardiac function in the adult heart and with pressure overload and that the absence of these molecules will lead to abnormal cardiac function that will be associated with abnormalities in intercalated .disc structure and function. Specific Aims: Aim 1: Determine the effect of cardiac specific and inducible CAR knockout on ventricular function in the adult heart during normal growth and with pressure overload. Aim 2: Determine the molecular and cellular mechanisms by which CAR disruption affects cardiac function with an emphasis on adjacent transmembrane proteins and sarcolemmal proteins that are located on the cytoplasmic side of the membrane within the intercalated disc. Specific Aim 3: Determine whether cardiac myocyte expression of ZO-1 is required for formation of the normal embryonic heart and its role in normal cardiac function and intercalated disc formation in the adult heart.

间盘（ICD）是主要的心肌细胞-细胞粘附结构，其将肌细胞连接到 彼此它们由一系列蛋白质组成，这些蛋白质被分为三个主要的连接蛋白。 复合体、粘连筋膜连接、桥粒和缝隙连接，并且对于维持 相邻肌细胞之间的机械和电耦合/椎间盘中的椎间盘突出 与遗传性扩张型心肌病有关， 语言障碍/心肌病（ARVD/C）。在文献中也报道了闰盘的异常。 心肌病的背景。柯萨奇病毒腺病毒受体（CAR）主要定位于 在成人心脏的椎间盘。虽然我们和其他人已经证明CAR表达是 尽管CAR在正常的心血管发育中起重要作用，但对CAR及其功能的意义知之甚少。 相关分子在成人心脏和正常闰盘的形成。底层 该项目的假设是CAR和ZO-1表达是正常心脏功能所必需的。 成年人的心脏和压力超负荷，缺乏这些分子会导致心脏异常 与闰盘结构和功能异常相关的功能。 具体目标： 目的1：确定心脏特异性和诱导性CAR敲除对心肌梗死患者心室功能的影响。 正常生长和压力超负荷的成年心脏。 目的2：确定CAR破坏影响心脏功能的分子和细胞机制 重点是位于细胞膜上的相邻跨膜蛋白和肌膜蛋白。 在闰盘内的膜的细胞质侧。 具体目标3：确定心肌细胞ZO-1的表达是否是形成心肌细胞凋亡所必需的。 正常胚胎心脏及其在成人心脏功能和闰盘形成中的作用 心