Molecular Mechanisms of Cell-Cell Attachment

细胞与环境之间的黏附相互作用对细胞寿命的几乎所有方面都是至关重要的。它们直接调节细胞向组织和器官的组装，控制细胞的运动，影响细胞的形状，并协调多种跨膜信号网络的激活，这些信号网络决定细胞的行为和命运。细胞迁移和细胞间黏附之间的平衡是至关重要的，特别是当细胞在发育过程中迁移到特定位置时。当细胞彼此接触时，细胞会变得静止，并分化成组织，对这些组织来说，细胞与细胞之间的粘连是维持组织完整性所必需的。另一方面，细胞间黏附的变化重新启动细胞迁移，以允许细胞周转，例如伤口愈合所必需的细胞周转。该项目试图通过研究关键调节因子α-连环蛋白来促进我们对细胞-细胞黏附的理解，该调节因子作为细胞-细胞连接力的关键传感器发挥作用。这项工作将为我们进一步从机制上理解不同的α-连环蛋白功能状态提供结构性的见解。此外，该项目还包括针对代表性不足的少数群体，特别是年轻群体的教育宣传部分，包括为7年级和8年级学生设立的动手讲习班：DNA提取讲习班和药物发现讲习班；研究人员参加由小威廉·R·凯南资助的高中生暑期实习方案。慈善信托基金在那里为高中生提供为期六周的暑期辅导并提供实践研究经验；以及研究生项目教师聘任的PI。本研究项目将使用第一台300KV低温原子分辨显微镜(CryoARM300)，在脂筏和非RAFT膜条件下提供α-连环蛋白的新的近原子分辨结构。这项工作是阐明与肌动蛋白细胞骨架结合的各种α-连环蛋白状态的机制和特定功能的第一步。生化和细胞分析将进一步验证结构发现。因此，这个项目将产生对细胞-细胞黏附的重大机械性见解。该项目由生物科学中分子和细胞生物科学部的分子生物物理学和细胞动力学和功能群支持。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Adhesive interactions between cells and their environment are crucial for nearly all aspects of the life of cells. They directly regulate the assembly of cells into tissues and organs, control cell motility, affect cell shape, and orchestrate the activation of diverse transmembrane signaling networks which determine the behavior and fate of cells. The balance between cell migration and cell-cell adhesion is crucial in particular when cells migrate to specific sites during development. Upon contact with each other, cells become stationary and differentiate into tissues for which strong cell-cell adhesion is necessary to maintain tissue integrity. On the other hand, changes in cell-cell adhesion reinitiate cell migration to allow cell turnover necessary for example for wound healing. The project seeks to advance our understanding of cell-cell adhesion by studying the key regulator, alpha-catenin, that functions as a crucial sensor of force of cell-cell junctions. This work will provide structural insights to further our mechanistic understanding of the distinct alpha-catenin functional states. Additionally, this project includes an educational outreach component geared towards the underrepresented minorities and in particular the younger population, including an established hands-on workshops for 7th and 8th graders: a DNA extraction workshop and a drug discovery workshop; the researchers' participation in the High School Student Summer Internship Program funded by the William R. Kenan, Jr. Charitable Trust where the mentor high school students for six weeks in the Summer and provide hands-on research experience; and the Graduate Program faculty appointment of the PI. This research project will use the first 300 kV cryogenic Atomic Resolution Microscope (cryoARM300) to provide new near atomic resolution structures of alpha-catenin in lipid raft and non-raft membrane conditions. This work is a first step in elucidating the mechanism and specific functions of various alpha-catenin states that bind to the actin cytoskeleton. Biochemical and cellular assays will additionally validate the structural findings. Thus, significant mechanistic insights into cell-cell adhesion will result from this project. This project is supported by the Molecular Biophysics and Cellular Dynamics and Functions Clusters of the Division of Molecular and Cellular Biosciences in Biological Sciences Directorate.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.