Decoding cortical Notch signaling and morphogenic instruction at cell-cell interfaces

解码细胞-细胞界面的皮质Notch信号传导和形态发生指令

基本信息

批准号：
10714471
负责人：
Matthew L Kutys
金额：
$ 40.38万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-20 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10714471
关键词：
3-Dimensional Actins Adhesions Adhesives Architecture Area Behavior Biological Process Biomimetics Biophysics Cardiovascular Diseases Cell Communication Cell-Cell Adhesion Cells Complex Crowding Development Disease Endothelial Cells Engineering Epithelium Exposure to Extracellular Matrix Family Gene Expression Genetic Genetic Processes Genetic Transcription Goals In Vitro Instruction Investigation Laboratories Malignant Neoplasms Mechanics Methods Microfluidics Microscopy Molecular Natural regeneration Output Pathology Pathway interactions Phenotype Postdoctoral Fellow Process Proteomics Research Signal Transduction Structure System Technology Time Tissues arm cell behavior cell cortex combat design gene regulatory network human model human tissue in vivo insight interdisciplinary approach next generation notch protein operation physical process programs receptor shear stress technology platform tool

项目摘要

Project Summary/Abstract The coordination of genetic programs and the physical organization of cells sculpt developing tissues, drive regeneration and, when dysregulated, facilitate disease. How these two processes are coordinated in space and time is poorly understood. Cell-cell interfaces are important organizing centers for morphogenic instruction. Here signals influencing gene expression that ultimately dictate cell fate decisions are integrated with changes in cell mechanics and, together, are necessary to build and maintain multicellular architectures. With an appreciation that gene regulatory networks and mechanics conspire at cell-cell interfaces to instruct morphogenic processes, an emerging challenge is to experimentally define the details of their intersectional operations in diverse morphogenic contexts. One intriguing example of cell-cell communication is the ubiquitously important Notch receptor pathway which has the intrinsic capacity to regulate both cell mechanics and gene expression, yet mechanisms of these distinct activities are unclear. As a postdoctoral fellow, the PI developed biomimetic microfluidic models of human tissues that were employed to identify several new mechanisms controlling 3D multicellular behavior operating at cell-cell and cell-extracellular matrix interfaces. The PI discovered that the highly conserved Notch family of receptors possess a previously undescribed cortical signaling function that permits Notch to connect changes in cell mechanics to transcriptional output. As an independent laboratory, the Kutys Lab has completed the first investigation into cortical Notch signaling in epithelial tissues and has identified morphogenic consequences and previously unappreciated signaling mechanisms. Over the next five years, the goal of the Kutys Lab is to continue its multidisciplinary approach of developing next generation biomimetic human tissue systems, molecular technologies, and microscopy-based methods to define the coordination of morphogenic behavior and signaling at cell adhesive interfaces. We will focus these efforts in three Areas: 1) engineering new tools to deeply understand how the cortical Notch pathway regulates signaling and adhesion mechanics in epithelia and the contexts in which it is invoked to regulate important biological processes in vitro and in vivo, 2) comprehensively defining how Notch receptor localization and activation are influenced by biophysical interactions with cell-cell adhesions and cortical actin during epithelial crowding and in endothelial cells exposed to shear stress, and 3) integrating proteomic approaches with 3D biomimetic systems to broadly profile and dissect how tissue architecture influences molecular control systems operating at cell-cell interfaces. The results of this research and the integration of the enabling technologies will contribute to the overall objectives of my research program. Together, these studies will offer fundamental insight into an important new arm of Notch signaling, how cell-cell adhesions might be dynamically regulated, and the molecular basis for how transcriptional and adhesive programs might be coordinated within complex 3D tissues.

项目概要/摘要遗传程序和细胞物理组织的协调塑造了发育中的组织，驱动再生，当失调时，会促进疾病。这两个过程如何在空间上协调对时间的了解甚少。细胞-细胞界面是形态发生指令的重要组织中心。这里影响最终决定细胞命运决定的基因表达的信号与细胞的变化相结合力学和共同作用是构建和维护多细胞架构所必需的。带着欣赏的心情基因调控网络和机制在细胞-细胞界面上共同指导形态发生过程，一个新出现的挑战是通过实验来定义不同领域的交叉操作的细节形态发生环境。细胞间通信的一个有趣的例子是无处不在的重要Notch 受体途径具有调节细胞力学和基因表达的内在能力，但这些不同活动的机制尚不清楚。作为博士后研究员，PI 开发了仿生技术人体组织的微流体模型，用于识别控制 3D 的几种新机制在细胞-细胞和细胞-细胞外基质界面上操作的多细胞行为。 PI 发现高度保守的Notch受体家族具有先前未描述的皮质信号传导功能允许Notch将细胞力学的变化与转录输出联系起来。作为一个独立的实验室， Kutys 实验室已经完成了对上皮组织中皮质 Notch 信号传导的首次研究，并确定了形态发生的后果和以前未被认识到的信号机制。未来五年内， Kutys 实验室的目标是继续采用多学科方法开发下一代仿生材料人体组织系统、分子技术和基于显微镜的方法来定义协调细胞粘附界面的形态发生行为和信号传导。我们将把这些努力集中在三个领域：1) 设计新工具来深入了解皮质 Notch 通路如何调节信号传导和粘附上皮细胞的力学及其在体外调节重要生物过程的背景和体内，2）全面定义Notch受体定位和激活如何受到影响上皮拥挤和内皮细胞中细胞间粘附和皮质肌动蛋白的生物物理相互作用暴露于剪切应力的细胞，以及 3) 将蛋白质组学方法与 3D 仿生系统相结合，以广泛剖析和剖析组织结构如何影响在细胞-细胞界面上运行的分子控制系统。这项研究的结果以及使能技术的整合将有助于整体我的研究计划的目标。总之，这些研究将为一个重要的新领域提供基本见解。 Notch 信号传导臂，细胞间粘附如何动态调节，以及如何动态调节的分子基础转录和粘附程序可能在复杂的 3D 组织内协调。