Notch signaling and adhesion regulation

Notch信号传导和粘附调节

基本信息

批准号：
10164623
负责人：
CHRISTOPHER S CHEN
金额：
$ 41.25万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10164623
关键词：
Address Adherens Junction Adherent Culture Adhesions Adhesives Animals Biological Biomimetics Blood Blood Vessels Blood flow CD45 Antigens Cell Adhesion Cell Lineage Cell-Matrix Junction Cells Cellular Structures Chemicals Chimera organism Cleaved cell Clustered Regularly Interspaced Short Palindromic Repeats Complex Coupled Dermal Development Disease Ductal Epithelium Endothelial Cells Endothelium Engineering Extracellular Matrix Family Feedback Gene Expression Profile Genetic Genetic Processes Genetic Transcription Goals Human Human Engineering Image Inflammatory Integrins Intercellular Junctions Left Ligand Binding Ligands Link Lymphatic Maintenance Malignant Neoplasms Measurement Mechanics Mediating Mediator of activation protein Microfluidic Microchips Modeling Molecular Monitor Morphogenesis Movement Notch Signaling Pathway Pathogenesis Pathway interactions Pattern Perfusion Phenotype Phosphoric Monoester Hydrolases Physiology Play Proteins Proteolysis Receptor Signaling Regulation Research Personnel Role Signal Pathway Signal Transduction Sorting - Cell Movement Stress Structure System Time Tissues Transcription Coactivator Transmembrane Domain Vascular Permeabilities Work arm base cadherin 5 design genome editing hemodynamics insight mammary epithelium mutant notch protein novel optogenetics physical process programs receptor shear stress spatiotemporal synthetic biology tool transcription factor

项目摘要

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.

项目描述和总结该提案的目标是描述一种新机制，通过该机制，Notch 受体调节细胞粘附动力学的变化。 Notch信号传导高度保守整个动物界在发育过程中调节细胞命运，其失调已与多种血管炎症性疾病、发育异常、和癌症。配体与Notch受体的结合导致蛋白水解裂解，从而释放细胞内结构域（ICD）作为转录激活剂，这种机制已被主要重点描述Notch在发育和疾病中的作用。调查员有最近发现，血流引起的剪切应力会激活Notch，进而导致内皮细胞-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物的形成集会。在这里，研究者将识别组件、潜在机制和这种以前未被认识到的 Notch 非转录皮质通路对细胞的影响并阐明该途径所涉及的生物学背景。这些目标将是通过围绕三个目标建立的跨学科计划来实现：具体目标 1 将是定义非典型皮质 Notch 信号通路的潜在机制。具体目标图 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 是探索皮质 Notch 通路推广到的程度更广泛的生物学背景。总之，这些研究将为这一新的研究提供重要的见解。 Notch 信号传导臂，并为转录和粘附的方式提供分子基础程序可能由单个受体协调。