Notch signaling and adhesion regulation

项目描述和摘要 该提案的目标是描述一种新的机制， 受体调节细胞粘附动力学的变化。Notch信号是高度保守的 在整个动物王国中调节细胞在发育过程中的命运，它的失调 与多种血管炎性疾病，发育异常， 和癌症。配体与Notch受体的结合导致蛋白水解裂解，其释放Notch受体。 细胞内结构域（ICD）作为转录激活因子，这种机制一直是 主要集中在描述Notch在发育和疾病中的作用。研究者已 最近发现，血流引起的剪切应力激活Notch，这反过来又导致 内皮细胞-细胞连接的快速组装和增强的屏障功能。在这项工作中， 他们证明了Notch蛋白水解后留下的跨膜结构域（TMD） 启动负责刺激连接的皮质信号复合体的形成 组装件.在这里，研究人员将确定组件，潜在的机制， 这种以前未被认识到的非转录、皮质途径对Notch的细胞影响 并阐明这一途径参与的生物学背景。这些目标将 通过围绕三个目标建立的跨学科计划实现：具体目标1将是 定义非经典皮质Notch信号通路的潜在机制。具体目标 2将检查粘附、力和皮质Notch信号通路之间的串扰。 具体目标3将是探索皮质Notch通路推广到 更广泛的生物学背景。总之，这些研究将提供重要的见解， 臂的Notch信号，并提供了分子基础，如何转录和粘附 程序可以由一个单一的受体来协调。

Project Description and Summary The goal of this proposal is to characterize a new mechanism by which the Notch receptor regulates changes in cell adhesion dynamics. Notch signaling is highly conserved across the animal kingdom to regulate cell fates during development, and its dysregulation has been implicated in a variety of vascular inflammatory diseases, developmental abnormalities, and cancers. Binding of ligand to Notch receptor leads to proteolytic cleavages that release the intracellular domain (ICD) as a transcriptional activator, and this mechanism has been the primary focus in describing the role of Notch in development and disease. The investigator has recently found that shear stress caused by blood flow activates Notch, which in turn leads to rapid assembly of endothelial cell-cell junctions and heightened barrier function. In this work, they demonstrated that the transmembrane domain (TMD) left behind after Notch proteolysis initiates the formation of a cortical signaling complex that is responsible for stimulating junction assembly. Here, the investigator will identify the components, underlying mechanisms, and cellular impact of this previously unappreciated non-transcriptional, cortical pathway for Notch and elucidate the biological contexts in which this pathway is engaged. These objectives will be achieved through an interdisciplinary program built around three Aims: Specific Aim 1 will be to define mechanisms underlying the non-canonical cortical Notch signaling pathway. Specific Aim 2 will examine crosstalk between adhesion, force, and the cortical Notch signaling pathway. Specific Aim 3 will be to explore the extent to which the cortical Notch pathway generalizes to broader biological contexts. Together, these studies will offer important insights into this new arm of Notch signaling, and provide a molecular basis for how transcriptional and adhesive programs might be coordinated by a single receptor.