Role of ADAMs in Heart Myocyte Development

描述(申请人提供)：脊椎动物心脏的发育是 依赖于许多细胞过程，包括迁移、增殖、 分化和细胞凋亡。这些过程的当务之急是交互 相邻细胞之间以及细胞与周围细胞外之间 矩阵。去整合素和金属蛋白酶(ADAMS)是近年来发现的一种 已识别的细胞表面蛋白家族，被认为是介导 细胞间的相互作用，并在蛋白质降解中发挥重要作用 细胞外基质成分和其他细胞表面分子的裂解。 到目前为止，至少有30名亚当斯被确认为 多结构域包括金属蛋白酶、去整合素、富含半胱氨酸、 表皮生长因子样区、跨膜区和胞质区。我们有 最近确定了几种ADAM在心肌细胞中的表达； 然而，它们在心肌细胞发育中的作用尚未确定。基于 在其他系统中发表的文献和提供的初步数据 在这里，我们假设亚当斯通过他们的多域结构，扮演 在心肌细胞发育和组织中的重要作用。此外，我们 假设亚当斯和亚当斯的金属蛋白酶活性定位 ADAM介导的细胞间相互作用对正常心肌细胞是必不可少的 发展。为验证这些假设而设计的实验目标包括： 1)确定特定ADAMS表达的变化是否影响 心肌细胞的分化、组织或功能；2)确定 ADAM金属蛋白酶活性在心肌细胞组织中的功能作用 和成熟；3)确定ADAM介导的细胞-细胞的作用 调控心肌细胞发育和组织的相互作用。这些研究 将阐明这个新的蛋白质家族成员在 发育中心脏中的心肌细胞分化和组织。

DESCRIPTION (provided by applicant): Development of the vertebrate heart is dependent on a number of cellular processes including migration, proliferation, differentiation and apoptosis. Imperative to these processes are interactions between adjacent cells and between cells and the surrounding extracellular matrix. The A Disintegrin And Metalloproteases (ADAMs) are a recently identified family of cell surface proteins that are thought to mediate cell-cell interactions and to play significant roles in the proteolytic cleavage of extracellular matrix components and other cell surface molecules. There are at least 30 ADAMs identified to date which are all characterized by a multidomain structure including metalloprotease, disintegrin, cysteine-rich, epidermal growth factor-like, transmembrane and cytoplasmic domains. We have recently determined that several ADAMs are expressed by heart myocytes; however, their roles in myocyte development have not been determined. Based on the published literature in other systems and the preliminary data presented here, we hypothesize that ADAMs, through their multidomain structure, play essential roles in cardiomyocyte development and organization. Furthermore, we hypothesize that localized metalloprotease activity by the ADAMs and ADAM-mediated cell-cell interactions are imperative to normal myocyte development. The experimental aims designed to test these hypotheses include: 1) to determine whether alterations in expression of specific ADAMs affects the differentiation, organization or function of heart myocytes; 2) to determine the functional roles of ADAM metalloprotease activity in myocyte organization and maturation; and 3) to determine the roles of ADAM-mediated cell-cell interactions in modulating myocyte development and organization. These studies will elucidate the roles of members of this novel protein family in cardiomyocyte differentiation and organization in the developing heart.