Adhesion Molecules of the Intercalated Disc in Cardiomyopathy

心肌病闰盘的粘附分子

• 批准号: 7331346
• 负责人: Kirk U Knowlton
• 金额: $ 62.08万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7331346
• 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; Disruption; Dysphasia; Embryo; Embryonic Heart; Epithelial Cells; Extracellular Matrix; Fascia; Fascia adherens; Gap Junctions; Genetic Recombination; Growth; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Human; Immunoglobulin Domain; Inherited; Integral Membrane Protein; Intercalated disc; Intercellular Junctions; Investigation; Knock-out; Knockout Mice; Laboratories; Lead; Learning; Link; Localized; Location; Mechanics; Mediating; Membrane; Microfilaments; Molecular; Mus; Muscle Cells; Myocardium; Myosin Heavy Chains; N-Cadherin; Pathogenesis; 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.

NTERCATACAT的椎间盘（ICD）是主要的心脏细胞 - 细胞粘附结构，将肌肉细胞连接到 彼此。它们由一系列蛋白质组成，这些蛋白质分为三个主要连接处 复合物，筋膜膜连接，脱染色和间隙连接，对于维持 相邻的肌肉细胞/异常之间的机械和电耦合 与遗传性心肌病的遗传形式有关，例如心律不齐右心室 心障/心肌病（ARVD/ C）。同样在插入式椎间盘的异常也报告了 心肌病的设置。 Coxsackievivirus腺病毒受体（CAR）主要定位于 成人心脏中的椎间盘。虽然我们和其他人都表明需要汽车表达 正常的心血管发育，相对较少知道汽车及其功能意义 成人心脏中的相关分子并形成正常的插入式椎间盘。基础 该项目的假设是在正常心脏功能中需要汽车和ZO-1表达 成人心脏和压力超负荷，没有这些分子会导致心脏异常 与插入的.DISC结构和功能中异常相关的功能。 具体目的： 目标1：确定心脏特异性和诱导型汽车敲除对心室功能的影响 在正常生长和压力超负荷的情况下，成人心脏。 目标2：确定汽车破坏会影响心脏功能的分子和细胞机制 强调位于 膜的膜的细胞质侧。 特定目标3：确定ZO-1的心肌细胞表达是否需要形成 正常的胚胎心脏及其在成人正常心脏功能和插入椎间盘形成中的作用 心。