CELL/ECM INTERACTIONS IN CARDIAC VALVULOSEPTAL MORPHOGENESIS

细胞与细胞外基质（extracellular matrix， ECM）之间的相互作用调节着迁移、增殖和分化的基本过程，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、相互的，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。提出的研究将解决的假设是，心脏的细胞成分和ECM之间的动态相互作用，这是至关重要的瓣膜间隔形态发生。参与这些相互作用的分子的表达、积累或组织的改变有助于瓣膜间隔组织的畸形。以下具体目标将用于验证这一假设：1)确定β 1亚家族的特定整合素在调节粘附、迁移、ECM组织和与瓣膜间隔发育相关的机械张力产生中的功能；2)研究特定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；3)确定基质金属蛋白酶和独特的A崩解素和金属蛋白酶（ADAM）蛋白在瓣膜间隔发育中的ECM重塑作用。我们将使用多种细胞和分子技术结合体内和体外试验来确定参与细胞- ecm相互作用的分子的功能意义。这些研究将测试特定ECM成分、它们的受体和ECM修饰蛋白酶在调节瓣膜间隔组织（包括心垫间充质细胞和心外膜源性细胞）的细胞行为中的功能作用。这些研究将进一步促进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导致先天性心脏病。

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.