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

 描述（由申请人提供）：颅神经嵴（CNC）细胞是有助于脊椎动物颅面结构和心脏组织的干细胞/祖细胞。CNC发育中最早和最关键的阶段之一是CNC的特化，其需要转录因子Snail 2的诱导，这一过程也被癌细胞用于触发其侵袭。因此，了解CNC规范的基本机制对于开发预防和治疗CNC相关出生缺陷和肿瘤侵袭的新方法至关重要。本申请的目的是阐明两种去整合素金属蛋白酶（ADAM）亚当斯13和19在CNC规范中发挥作用的分子途径。该申请有三个具体目标。第一个目的是确定ADAM 13在调节经典Wnt信号传导中的作用。要测试的假设是，ADAM 13切割和失活两个肝配蛋白-B，其功能作为典型的Wnt信号传导，一个主要的信号传导途径，是CNC规范必不可少的新型拮抗剂。第二个目标是确定ADAM 19在CNC规范中的作用机制，重点是亚当斯13和19之间的功能相互作用。在第三个目标中，候选和基因组方法将用于鉴定ADAM-ephrin-Wnt信号传导轴的下游转录靶点。这项研究的结果将为ADAM蛋白酶，ephrin-Bs和Wnt信号传导的相互作用提供新的见解，这是CNC发展和癌侵袭中的三个重要调控元件。基于这些信息，可以开发新的方法来诱导CNC细胞用于治疗目的或抑制癌侵袭。

 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.