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) 细胞是对脊椎动物颅面结构和心脏组织做出贡献的干细胞/祖细胞。CNC 发育的最早和最关键的阶段之一是 CNC 的规范，它需要诱导转录因子 Snail2，癌细胞也利用这一过程来触发其侵袭。因此，了解 CNC 规范的基本机制对于开发预防和治疗 CNC 相关出生缺陷和癌症侵袭的新方法至关重要。当前申请的目标是阐明 ADAM 13 和 19（两种解整合素金属蛋白酶 (ADAM)）在 CNC 规范中发挥作用的分子途径。该应用程序具有三个具体目标。第一个目标是确定 ADAM13 在调节经典 Wnt 信号传导中的作用。待测试的假设是 ADAM13 裂解并灭活两个 ephrin-B，这两个 ephrin-B 是经典 Wnt 信号传导的新型拮抗剂，而 Wnt 信号传导是 CNC 规范所必需的主要信号传导途径。第二个目标是确定 CNC 规范中 ADAM19 的作用机制，重点是 ADAM 13 和 19 之间的功能相互作用。第三个目标是使用候选方法和基因组方法来识别 ADAM-ephrin-Wnt 信号轴的下游转录靶标。这项研究的结果应该为 ADAM 蛋白酶、肝配蛋白 B 和 Wnt 信号传导（CNC 发育和癌症侵袭中的三个重要调节元件）之间的相互作用提供新的见解。基于这些信息，可以开发新方法来诱导 CNC 细胞用于治疗目的或抑制癌症侵袭。

 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.