A conserved ADAM-ephrin-Wnt signaling axis in neural crest development and cancer

 描述(申请人提供)：脑神经脊细胞(Cnc)是促进脊椎动物头面部结构和心脏组织发育的干/祖细胞。Cnc发展的最早和最关键的阶段之一是Cnc的规范，这需要诱导转录因子Snail2，这一过程也被癌细胞用来触发它们的侵袭。因此，了解计算机数控系统规范的基本机制对于开发预防和治疗计算机数控系统相关出生缺陷和肿瘤侵袭的新方法至关重要。目前应用的目标是阐明两个去整合素金属蛋白酶(ADAMS)Adams 13和19在CNC规范中发挥作用的分子途径。该应用程序有三个具体目标。第一个目的是确定ADAM13在调节规范的Wnt信号中的作用。需要检验的假设是，ADAM13裂解并失活两个ePhin-B，它们作为规范Wnt信号的新拮抗剂发挥作用，这是一条对CnC规范至关重要的主要信号通路。第二个目标是确定ADAM19在CnC规范中的作用机制，重点将放在ADAM13和19之间的功能相互作用上。第三个目标是用候选和基因组方法来确定Adam-eaffin-Wnt信号轴的下游转录靶点。这项拟议的研究结果将为亚当蛋白水解酶、ePhin-B和Wnt信号的相互作用提供新的见解，这三个信号是计算机控制系统发育和肿瘤侵袭的重要调节元件。基于这些信息，可能会开发出新的方法来诱导CNC细胞用于治疗目的或抑制肿瘤的侵袭。

 DESCRIPTION (provided by applicant): The cranial neural crest (CNC) cells are stem/progenitor cells that contribute to the vertebrate craniofacial structures and cardiac tissues One of the earliest and most critical stages in CNC development is the specification of the CNC, which requires induction of the transcription factor Snail2, a process that is also used by carcinoma cells to trigger their invasion. Therefore, understanding the basic mechanisms for CNC specification is critical for developing new methodologies for the prevention and treatment of CNC-related birth defects and carcinoma invasion. The goal of the current application is to elucidate the molecular pathways through which ADAMs 13 and 19, two disintegrin metalloproteinases (ADAMs), function in CNC specification. The application has three specific aims. The first aim is to define the roles of ADAM13 in regulating canonical Wnt signaling. The hypothesis to be tested is that ADAM13 cleaves and inactivates two ephrin-Bs, which function as novel antagonists of canonical Wnt signaling, a major signaling pathway that is essential for CNC specification. The second aim is to determine the mechanism of action for ADAM19 in CNC specification, and the focus will be on the functional interaction between ADAMs 13 and 19. In the third aim, both candidate and genomic approaches will be used to identify the downstream transcriptional targets of the ADAM-ephrin-Wnt signaling axis. Outcomes of this proposed research should provide new insight into the interactions of ADAM proteases, ephrin-Bs and Wnt signaling, three important regulatory elements in CNC development and carcinoma invasion. Based on this information, new methods may be developed to induce CNC cells for therapeutic purposes or inhibit carcinoma invasion.