INTERACTION OF PDGF AND INTEGRINS IN THE HEART

外在和内在信号调节着时间和空间 表达对正常心脏发育至关重要的基因。这个 导致细胞内和细胞内蛋白的精确表达 心脏特有的细胞外成分。这个 这些基因的协同表达导致形成正常的 而这种异常表达可能会导致心脏畸形 心。在细胞外信号中，重要的是 细胞外基质(ECM)和生长因子调节两者 心肌细胞的增殖和生长。这两种生长的受体 因子和ECM成分在调控中发挥着不可或缺的作用 心脏发育。虽然有多种增长因素可以 体内调控作用及其与特异性细胞外基质的协同表达 受体，整合素，必须首先在体外进行评估，以便 了解细胞生长发育的调控机制(S)。 拟议的调查将解决这样的假设：血小板 衍生生长因子受体(PDGFR)亚型不同 在肌细胞和成纤维细胞上表达，并在不同的刺激下 PDGF的异构体影响整合素的表达，进而改变整合素的表达 所有的黏附和迁移。为了解决这一假设，我们将检验 具体目标如下：1)确定时间和空间 心脏缺陷在PDGFR和PDGFR细胞水平的表达 配体转基因小鼠；2)调控PDGF受体的表达 和整合素的体外表达，以确定改变表达的影响 肌细胞和成纤维细胞的生长和功能；3)恢复 用腺病毒载体进行体外功能实验 从PDGF受体基因敲除小鼠分离的细胞；以及4)调节 血小板衍生生长因子受体和整合素在全胚胎培养中的表达 确定它们在心脏发育中的作用。这些实验将，为 首次确定了PDGF异构体和受体亚型的作用 在细胞过程中，如肌纤维形成、细胞黏附和 迁移，这是心脏正常发育所必需的。

Extrinsic and intrinsic signals regulate the temporal and spatial expression of genes that are essential for normal heart development. The results in the precisely orchestrated expression of both intracellular and extracellular components that are characteristic of the heart. The coordinate expression of these genes results in the formation of a normal heart while the aberrant expression may result in malformation of the heart. Significant among the extracellular signals are components of the extracellular matrix (ECM) and growth factors which regulate both proliferation and growth of the myocytes. Receptors for both growth factors and ECM components play a integral role in the regulation of cardiac development. While there are multiple growth factors that can have regulatory effects in vivo, their coordinate expression with specific ECM receptors, integrins, must be first assessed in vitro in order to understand the mechanism(s) that regulate cellular growth and development. The proposed investigations will address the hypothesis that Platelet Derived Growth Factor receptor (PDGFr) subtypes are differentially expressed on myocytes and fibroblasts and when stimulated by the different isoforms of PDGF affect the expression of integrins, which in turn alters ell adhesion and migration. To address this hypothesis, we will examine the following specific aims: 1) To determine the temporal and spatial expression of cardiac defects at the cellular level in the PDGFr and ligand transgenic mice; 2) To manipulate the expression of PDGF receptors and integrins in vitro to determine the affect of altered expression on growth and function of myocytes and fibroblasts; 3) To perform return of function experiments in vitro using adenovirus containing constructs and cells isolated from PDGF receptor knockout mice; and 4) To modulate the expression of PDGF receptors and integrins in whole embryo cultures to determine their role in cardiac development. These experiments will, for the first time determine the role of PDGF isoforms and receptor subtypes in cellular processes, such as myofibrillogenesis, cell adhesion and migration, that are essential to normal cardiac development.