SIGNAL TRANSDUCTION AND MOUSE DEVELOPMENT

生长因子诱导多种细胞反应，包括增殖、存活和迁移。许多生长因子激活具有内在酪氨酸激酶活性的受体。对细胞培养系统的广泛研究表明，受体结合会导致细胞内效应物的结合，并激活单个信号通路。然而，利用一种或另一种途径的生理相关性仍然是未知的。在这一建议中，我们将重点确定血小板衍生生长因子（PDGFs）下游个体信号通路的作用，PDGFs参与许多组织的发育和生理反应，包括脉管系统、肾脏、骨骼和神经嵴衍生物。我们将通过产生表达PDGF受体的突变小鼠来实现我们的目标，其中各种效应物的单个对接位点已经发生突变。我们将进一步集中精力，使用遗传替代方法确定PDGF受体和其他生长因子受体之间的信号通路是否冗余。为了进一步研究PDGF信号在发育中的作用，我们将使用条件基因消融来测试PDGF信号在特定组织中的作用。这些研究将有助于我们了解生长因子的调控机制，并为生理过程中生长因子信号通路的特异性和相互作用提供信息。

Growth factors induce a variety of cellular responses including proliferation, survival and migration. A number of growth factors activate receptors with intrinsic tyrosine kinase activity. Extensive studies in cell culture systems have shown that receptor engagement leads to binding of intracellular effectors, and the activation of individual signaling pathways. However, the physiological relevance of utilizing one or another pathway remains mostly unknown. In this proposal, we will focus on identifying the roles of individual signaling pathways downstream of platelet derived growth factors (PDGFs), which are involved in developmental and physiological responses in many tissues, including the vasculature, the kidney, the skeleton and neural crest derivatives. We will achieve our goals by generating mutant mice that express PDGF receptors in which the individual docking sites for various effectors have been mutated. We will further concentrate our efforts on determining if signaling pathways between PDGF receptors and other growth factor receptors are redundant, using genetic substitution methods. To further investigate the role of PDGF signaling in development, we will make use of conditional gene ablation to test the role of PDGF signaling in specific tissues. These studies should help us understand growth factor regulatory mechanisms, and provide information on the specificity and interplay of growth factor signaling pathways in physiological processes.