INTERACTION OF PDGF AND INTEGRINS IN THE HEART

外在和内在信号调节时间和空间 这些基因对心脏正常发育至关重要。的 导致细胞内和细胞外基因的精确协调表达， 心脏特有的细胞外成分。的 这些基因的协调表达导致正常的 而异常表达可导致心脏畸形， 心在细胞外信号中重要的是细胞外信号的成分。 细胞外基质（ECM）和调节两者的生长因子 肌细胞的增殖和生长。两种生长的受体 因子和ECM成分在调节 心脏发育虽然有多种增长因素可以 在体内的调节作用，它们与特定ECM的协调表达 受体，整合素，必须首先在体外评估， 了解调节细胞生长和发育的机制。 拟议的调查将解决血小板的假设 衍生的生长因子受体（PDGFr）亚型在肿瘤细胞中的表达存在差异。 在肌细胞和成纤维细胞上表达，当受到不同的 PDGF的同种型影响整合素的表达，整合素反过来改变 粘附性和迁移性。为了解决这个问题，我们将研究 具体目标如下：1）确定时间和空间 在PDGFr中在细胞水平上表达心脏缺陷， 配体转基因小鼠; 2）操纵PDGF受体的表达 和整合素的表达，以确定改变的表达对 肌细胞和成纤维细胞的生长和功能; 3）执行返回 使用含有腺病毒的构建体进行体外功能实验， 从PDGF受体敲除小鼠分离的细胞;和4）为了调节PDGF受体的表达， PDGF受体和整合素在整个胚胎培养物中的表达， 决定它们在心脏发育中的作用。这些实验将为 首次确定PDGF亚型和受体亚型的作用 在细胞过程中，如肌原纤维形成、细胞粘附和 迁移，这对正常的心脏发育至关重要。

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.