Cell-Cell Junctions and Epithelial Homeostasis

细胞-细胞连接和上皮稳态

• 批准号: 9247215
• 负责人: W. James Nelson
• 金额: $ 87.18万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9247215
• 关键词: Actins; Actomyosin; Address; Adhesions; Cadherins; Cell Cycle; Cell Cycle Regulation; Cell Nucleus; Cell Proliferation; Cell-Cell Adhesion; Cells; Characteristics; Complex; Contact Inhibition; Cytoskeleton; Disease; Epithelial; Epithelial Cells; Epithelium; Equilibrium; Gene Expression; Hereditary Disease; Homeostasis; Inhibition of Cell Proliferation; Integrins; Intercellular Junctions; Malignant Neoplasms; Mechanics; Mediating; Phosphotransferases; Regulation; Role; Signal Pathway; Signaling Protein; Testing; Tissues; Work; alpha catenin; base; beta catenin; cell motility; insight; migration; public health relevance; response; technology development

 DESCRIPTION (provided by applicant): The fundamental characteristic of epithelia is cell-cell adhesion, which regulates signaling pathways involved in cell organization, migration and gene expression. Disruption of cell-cell adhesion leads to loss of epithelial cell organization, increasd cell migration, and loss of contact-inhibition of cell proliferation, which are characteristic of mny genetic diseases including cancer. Thus the RATIONALE for our work is that a deep mechanistic understanding of cell-cell adhesion will provide fundamental insights into the regulation of epithelial tissue organization in normal and disease states. Our CENTRAL HYPOTHESIS is that cell-cell adhesion maintains epithelial homeostasis by controlling cytoskeleton organization and cell migration, and sequestering key signaling proteins that regulate cell proliferation. Our LONG- TERM OBJECTIVES are organized under 2 broad themes that address KEY CHALLENGES about: A. Mechanisms involved in cadherin-mediated cell-cell adhesion, cytoskeleton organization and regulation of cell migration; and B. Response of cell-cell adhesion complexes to perturbation by mechanical strain. Based on significant results and technology development during the preceding period of support, we can now address KEY QUESTIONS about: Theme A. The regulation of αE-catenin (A.1) and actin (A.2) dynamics during cell-cell adhesion, and the cross-talk between cadherin- and integrin-based adhesions that control the balance between cell-cell adhesion and migration (A.3); and Theme B. Upon mechanical strain and cell cycle re- entry, how β-catenin and Yap1 are Trans located to the nucleus (B.1), the role of actomyosin activity (B.2) and kinases (B.3) in activating β-catenin and Yap1, and the involvement of additional junction-mediated signaling pathways in cell cycle regulation (B.4). Completion of these studies will answer KEY QUESTIONS about the role of cell-cell adhesion in cytoskeleton organization and cell migration, and sequestering key signaling proteins that regulate cell proliferation. These studies address fundamental CHALLENGES in understanding the regulation of epithelial tissue organization in normal and disease states.

 描述（由申请人提供）：上皮细胞的基本特征是细胞-细胞粘附，它调节涉及细胞组织、迁移和基因表达的信号通路。细胞-细胞粘附的破坏导致上皮细胞组织丧失、细胞迁移增加、细胞增殖的接触抑制的丧失，这是包括癌症在内的许多遗传疾病的特征，因此我们工作的基本原理是对细胞间粘附的深入机制的理解。我们的中心假设是，细胞间粘附通过控制细胞骨架组织和细胞迁移以及隔离调节细胞增殖的关键信号蛋白来维持上皮稳态。术语目标分为两大主题，解决以下方面的主要挑战： A. 钙粘蛋白介导的细胞-细胞相关机制粘附、细胞骨架组织和细胞迁移的调节；以及 B. 细胞-细胞粘附复合物对机械应变扰动的响应 基于前期支持期间的重大成果和技术发展，我们现在可以解决以下关键问题： 主题 A。细胞间粘附过程中 αE-连环蛋白 (A.1) 和肌动蛋白 (A.2) 动力学的调节，以及基于钙粘蛋白和整合素之间的串扰。控制细胞间粘附和迁移之间平衡的粘附（A.3）；以及主题 B。在机械应变和细胞周期重新进入时，β-连环蛋白和 Yap1 如何反式定位到细胞核（B.1），肌动球蛋白活性 (B.2) 和激酶 (B.3) 在激活 β-连环蛋白中的作用 和 Yap1，以及细胞周期调节中其他连接介导的信号通路的参与 (B.4)。完成这些研究将回答有关细胞-细胞粘附在细胞骨架组织和细胞迁移中的作用以及隔离关键信号传导的关键问题。这些研究解决了理解正常和疾病状态下上皮组织的调节的基本挑战。