Notch signaling and adhesion regulation

Notch信号传导和粘附调节

• 批准号: 10450753
• 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
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10450753
• 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; 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

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 这种以前未被重视的 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领域提供重要的见解。 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。