CELL/ECM INTERACTIONS IN CARDIAC VALVULOSEPTAL MORPHOGENESIS

细胞和细胞外基质(ECM)之间的相互作用调节着基本的迁移、增殖和分化过程，因此在脊椎动物心脏的发育中起着至关重要的作用。这些相互作用是动态的、互惠的，似乎在时间和空间上受到调节。虽然细胞-ECM相互作用在心脏发育中很重要，但参与这些相互作用的成分的潜在功能仍有待阐明。建议的研究将解决这样的假设，即心脏的细胞成分和细胞外基质之间存在动态相互作用，这对瓣膜间隔的形态发生至关重要。参与这些相互作用的分子的表达、积累或组织的改变导致瓣膜间隔组织的畸形。我们将利用以下特定目标来验证这一假说：1)确定Beta1亚家族中特定的整合素在调节与瓣膜间隔发育相关的黏附、迁移、ECM组织和机械张力产生中的功能；2)研究特定的ECM成分在调节对瓣膜间隔组织发育至关重要的细胞过程中的作用；以及3)确定基质金属蛋白酶和独特的A去整合素和金属蛋白酶(ADAM)蛋白在瓣膜间隔发育中所起的作用。我们将使用多种细胞和分子技术，结合体内和体外试验，确定参与细胞-细胞外基质相互作用的分子的功能意义。这些研究将测试特定的细胞外基质成分、它们的受体和细胞外基质修饰蛋白酶在调节心脏垫间充质细胞和心外膜衍生细胞等瓣膜间隔组织细胞行为方面的功能作用。这些研究将进一步加深我们对正常瓣膜间隔形态发生的基本细胞机制的理解，以及细胞-ECM相互作用的变化如何有助于先天性心脏病的发生。

Interactions between cells and the extracellular matrix (ECM) regulate fundamental processes of migration, proliferation and differentiation and, thus play critical roles in the development of the vertebrate heart. These interactions are dynamic, reciprocal and appear to be regulated in a temporal and spatial manner. While it is clear that cell-ECM interactions are important in heart development, the underlying functions of the components involved in these interactions remain to be elucidated. The proposed studies will address the hypothesis that there are dynamic interactions between the cellular components of the heart and the ECM which are critical to valvuloseptal morphogenesis. Alterations in the expression, accumulation or organization of molecules involved in these interactions contribute to malformation of the valvuloseptal tissues. The following specific aims will be used to test this hypothesis: 1) to determine the function of specific integrins of the beta1 subfamily in the regulation of adhesion, migration, ECM organization and generation of mechanical tension associated with valvuloseptal development; 2) to investigate the roles of specific ECM components in modulating cellular processes critical to the development of the valvuloseptal tissues; and 3) to determine the role of ECM remodeling by the matrix metalloproteases and the unique A Disintegrin And Metalloprotease (ADAM) proteins in valvuloseptal development. We will use a variety of cell and molecular techniques combined with both in vivo and in vitro assays to determine the functional significance of molecules involved in cell-ECM interactions. These studies will test the functional roles of specific ECM components, their receptors and ECM-modifying proteases in modulating the behavior of cells that contribute to the valvuloseptal tissues including cardiac cushion mesenchymal cells and epicardial-derived cells. These studies will further advance our understanding of the basic cellular mechanisms underlying normal valvuloseptal morphogenesis and how changes in cell-ECM interactions may contribute to congenital heart disease.