Interaction of BMP, WNT and SHH in the Vertebrate Limb

脊椎动物肢体中 BMP、WNT 和 SHH 的相互作用

• 批准号: 6875578
• 负责人: Juan Carlos Izpisua Belmonte
• 金额: $ 56.4万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-11 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6875578
• 关键词: apoptosis; biological signal transduction; bone morphogenetic proteins; cadherins; chick embryo; extracellular; gene expression; genetically modified animals; glycoproteins; histogenesis; in situ hybridization; laboratory mouse; limbs; mesenchyme; molecular cloning; protein protein interaction; terminal nick end labeling; tissue /cell culture; transfection /expression vector; vertebrate embryology

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.

描述(由申请人提供)：BMP、WNT和HH成员 分泌因子超家族在胚胎发育中发挥重要作用 发育，并严重参与了各种人类先天性疾病 疾病和几种癌症。近年来，对这一问题的详细研究 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， 对人类疾病和退化过程的治疗。因此，有 有相当大的兴趣加深我们对网络的了解 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新基因，这些基因可能成为 治疗性干预。在这里，我们建议使用脊椎动物的肢芽作为一种 研究骨形态发生蛋白活动协调机制的模型系统， 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) 在控制细胞存活和细胞死亡方面。我们建议研究一下 脊椎动物关键环节调控中的BMF、WNT和SHH信号通路 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，特别是在程序化细胞的控制中 死亡(PCD)；2)确定BMP靶标和WNT拮抗剂Dkk1的作用 在小鼠和雏鸡肢芽中控制PCD；3)表征 SHH通路在细胞程序性死亡(PCD)调控中的作用 以及4)分离和鉴定BMP的新靶点， WNT/B-连环蛋白和SHH信号在鸡胚胎中的表达。我们将使用增益-和 功能丧失策略来剖析相互作用网络 BMPs、WNTs和HH在小鼠和雏鸡的四肢上工作。我们的建议需要 充分利用几十年来积累的百科全书知识 启动和维持肿瘤细胞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机构 这些信号通路之间的相互作用，更准确地定义 这些因素参与控制两个胚胎的过程 发展与疾病的发生和发展。