Interaction of BMP, WNT and SHH in the Vertebrate Limb

描述（由申请人提供）：BMP、WNT 和 HH 的成员 分泌因子超家族在胚胎发育过程中发挥重要作用 发育，并且还关键参与多种人类先天性 疾病和几种类型的癌症。近年来，详细研究 这些分泌因子触发的信号通路提供了有用的 已应用于研究、检测和（在某些情况下）的信息， 治疗人类疾病和退化过程。因此，有 对加深我们对网络的理解表现出极大的兴趣 协调这些信号通路的相互作用，希望 识别与人类病理有关的可能成为目标的新基因 治疗干预。在这里，我们建议使用脊椎动物的肢芽作为 研究协调 BMP 活动的机制的模型系统， WNT 和 SHH（Sonic Hedgehog）信号通路。我们的目标是进一步定义 这些分泌因子的作用（以及它们触发的信号通路） 控制细胞的存活和死亡。我们建议研究的作用 BMF、WNT 和 SHH 信号通路在脊椎动物关键方面的控制 肢体发育，通过： 1) 确定 BMP 假受体 BAMIBI 的作用 在小鼠和小鸡的肢芽中，特别是在程序细胞的控制中 死亡（PCD）； 2) 确定BMP靶点和WNT拮抗剂DKK1的作用 控制小鼠和鸡肢芽中的 PCD； 3）表征 SHH通路在控制程序性细胞死亡（PCD）中的活性 肢体； 4) 分离和表征 BMP 的新靶标， 鸡胚胎中的 WNT/B-连环蛋白和 SHH 信号传导。我们将使用增益和 功能丧失策略来剖析之间的相互作用网络 在小鼠和小鸡四肢中发挥作用的 BMP、WNT 和 HH。我们的建议需要 充分利用几十年来积累的百科全书式知识 启动和维持发育的分子和细胞机制 脊椎动物的肢芽。我们的工作有可能发现关键的监管 这些信号通路之间的相互作用，并更准确地定义 这些因素参与控制胚胎的过程 发育以及疾病的发生和进展。

DESCRIPTION (provided by applicant): Members of the BMP, WNT and HH superfamilies of secreted factors play important roles during embryonic development, and are also critically involved in a variety of human congenital diseases and several types of cancer. In recent years, detailed studies of the signaling pathways triggered by these secreted factors have provided useful information that has been applied to the study, detection and (in some cases), treatment of diseases and degenerative processes in humans. Thus, there is considerable interest in deepening our understanding of the network of interactions that coordinates these signaling pathways, with the hope of identifying new genes involved in human pathologies that may become targets of therapeutic intervention. Here, we propose to use the vertebrate limb bud as a model system to study the mechanisms that coordinate the activities of the BMP, WNT and SHH (Sonic Hedgehog) signaling pathways. Our aim is to further define the roles of these secreted factors (and the signaling pathways they trigger) in the control of cell survival and cell death. We propose to study the role of BMF, WNT and SHH signaling pathways in the control of key aspects of vertebrate limb development, by: 1) Determining the role of the BMP pseudoreceptor BAMIBI in mouse and chick limb buds, specifically in the control of programmed cell death (PCD); 2) Determining the role of the BMP target and WNT antagonist DKK1 in the control of PCD in mouse and chick limb buds; 3) Characterizing the activities of the SHH pathway in the control of programmed cell death (PCD) in the limb; and 4) Isolating and characterizing novel targets of BMP, WNT/B-catenin and SHH signaling in the chick embryo. We will use gain- and loss-of-function strategies to dissect the network of interactions between BMPs, WNTs and HH that operate in mouse and chick limbs. Our proposal takes full advantage of the encyclopedic knowledge accumulated over decades on the molecular and cellular mechanisms that initiate and maintain development of the vertebrate limb bud. Our work has the potential to uncover key regulatory interactions between these signaling pathways, and to define more precisely the involvement of these factors in processes that control both embryonic development and disease initiation and progression.