Bves Function in Cardiac Myogenesis

Bves 在心肌生成中的功能

• 批准号: 7598976
• 负责人: David M BADER
• 金额: $ 37.26万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7598976
• 关键词: Adhesions; Amino Acid Sequence; Biochemical; Biological; Cardiac; Cardiac Myocytes; Cell Adhesion; Cell Adhesion Molecules; Cell Communication; Cell Maintenance; Cell membrane; Cell-Cell Adhesion Inhibition; Cells; Congenital Heart Defects; Data; Development; Embryo; Embryonic Development; Epithelium; Event; Family; Gene Transfer Techniques; Generations; Heart; In Vitro; Integral Membrane Protein; Intercalated disc; Intercellular Junctions; Lead; Link; Maps; Membrane; Methods; Molecular; Molecular Genetics; Morphogenesis; Mus; Muscle Cells; Mutate; Mutation; Peptide Sequence Determination; Physiological; Play; Proteins; Regulation; Research Personnel; Role; Site; Structure; Testing; Transgenic Organisms; Work; cardiogenesis; in vitro Model; in vivo; myogenesis; novel; programs; protein function; protein transport; selective expression

DESCRIPTION (provided by applicant): Myocyte-myocyte interaction is essential for heart development and function. We have discovered a novel family of transmembrane proteins (Bves/Popeye) that has a highly conserved protein sequence. Our work demonstrates that Bves acts as a cell adhesion molecule and is essential for maintenance of cell-cell interaction. Additionally, Bves is one of the first proteins to localize to points of cell-cell contact. In heart development, Bves is first present around the entire myocyte membrane at the onset of development but is later restricted to the intercalated disc. From these data, we predict that Bves plays an essential and early role in the cascade of events regulating adhesion during cardiac morphogenesis and in the generation of the disc. We have identified two novel interaction domains within the protein that are critical for Bves function and potentially for heart development including generation of the intercalated disc. First, a specific domain that regulates Bves-Bves intracellular interaction has been defined. Deletion or mutation of this domain abolishes Bves-Bves interaction and leads to complete inhibition of cell-cell adhesion. Second, we have discovered that Bves interacts through its C-terminus with ZO1, an essential component of the intercalated disc. Using molecular and physiological challenges, we have determined that inhibition of Bves function destabilizes ZO1 at the cell membrane and disrupts cell junctions. From these data, we hypothesize that Bves has essential functions in myocyte adhesion during heart development and in the formation of the intercalated disc. Three interactive specific aims will test the roles of the Bves-Bves intracellular interaction domain and Bves-ZO1 interaction domain during cardiac myogenesis in vivo and in vitro. Transgenic expression of Bves mutated in these domains will determine protein function during remodeling of cardiogenic epithelium, trabeculation, compaction and formation of the intercalated disc. It is clear that aberrant cell adhesion can lead to severe heart defects and that malformation of the heart represents one of the largest and most deleterious groups of abnormalities in embryogenesis. Determining how embryonic myocytes interact is essential in understanding heart defect; in the proposed studies, we will elucidate Bves function in cardiac morphogenesis and disc formation but, in a larger sense, determine how myocyte- myocyte interaction governs heart development and function.

描述（由申请人提供）：肌细胞与肌细胞的相互作用对于心脏发育和功能至关重要。我们发现了一个新的跨膜蛋白家族（Bves/Popeye），其具有高度保守的蛋白质序列。我们的工作表明，Bves 作为细胞粘附分子，对于维持细胞间相互作用至关重要。此外，Bves 是最早定位于细胞与细胞接触点的蛋白质之一。在心脏发育过程中，Bves 在发育开始时首先存在于整个肌细胞膜周围，但随后仅限于闰盘。根据这些数据，我们预测 Bves 在心脏形态发生和椎间盘生成过程中调节粘附的级联事件中发挥着重要的早期作用。我们在该蛋白质中发现了两个新的相互作用域，它们对于 Bves 功能至关重要，并且可能对心脏发育（包括闰盘的生成）至关重要。首先，定义了调节 Bves-Bves 细胞内相互作用的特定结构域。该结构域的缺失或突变会消除 Bves-Bves 相互作用，并导致细胞间粘附的完全抑制。其次，我们发现 Bves 通过其 C 末端与 ZO1（闰盘的重要组成部分）相互作用。通过分子和生理学挑战，我们确定抑制 Bves 功能会破坏细胞膜上 ZO1 的稳定性并破坏细胞连接。根据这些数据，我们假设 Bves 在心脏发育过程中的心肌细胞粘附和闰盘的形成中具有重要功能。三个相互作用的特定目标将测试 Bves-Bves 细胞内相互作用结构域和 Bves-ZO1 相互作用结构域在体内和体外心肌生成过程中的作用。这些结构域中突变的 Bves 的转基因表达将决定心源性上皮重塑、小梁形成、压实和闰盘形成过程中的蛋白质功能。很明显，异常的细胞粘附可导致严重的心脏缺陷，并且心脏畸形代表胚胎发生中最大和最有害的异常群体之一。确定胚胎肌细胞如何相互作用对于了解心脏缺陷至关重要。在拟议的研究中，我们将阐明 Bves 在心脏形态发生和椎间盘形成中的功能，但从更大的意义上讲，确定肌细胞-肌细胞相互作用如何控制心脏发育和功能。