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起重要作用 发育，并且还严重参与各种人类先天性 疾病和几种癌症。近年来，详细的研究 由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， 对加深我们对网络的理解有很大的兴趣， 协调这些信号通路的相互作用， 识别参与人类病理学的新基因，这些基因可能成为治疗的目标 治疗干预在这里，我们建议使用脊椎动物的肢芽作为一个 模型系统来研究协调BMP活动的机制， 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） 控制细胞存活和死亡。我们建议研究 BMF、WNT和SHH信号通路在脊椎动物基因调控中的关键作用 1）确定BMP假受体BAMIBI的作用 在小鼠和小鸡的肢芽中，特别是在控制编程细胞 2）确定BMP靶和WNT拮抗剂DKK 1的作用 在小鼠和鸡肢芽中的PCD控制中; 3）表征 SHH途径在控制程序性细胞死亡（PCD）中的活性， 肢体;和4）分离和表征BMP的新靶标， 鸡胚中的WNT/B-catenin和SHH信号传导。我们将使用增益-和 功能丧失战略，剖析网络之间的互动， 在小鼠和小鸡肢体中起作用的BMP、WNT和HH。我们的建议需要 充分利用几十年来积累的知识， 分子和细胞机制，启动和维持发展的 脊椎动物的肢芽我们的工作有可能揭示关键的监管 这些信号通路之间的相互作用，并更精确地定义 这些因素参与了控制胚胎发育和发育的过程， 疾病的发生和发展。

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.