Cell-Cell Junctions and Epithelial Homeostasis

 描述(申请人提供)：上皮细胞的基本特征是细胞间的黏附，它调节细胞组织、迁移和基因表达所涉及的信号通路。细胞间黏附的破坏会导致上皮细胞组织丧失，细胞迁移增加，失去接触抑制细胞增殖的能力，这些都是包括癌症在内的多种遗传性疾病的特征。因此，我们工作的基本原理是，深入理解细胞-细胞黏附的机制将为正常和疾病状态下上皮组织的调节提供基本的见解。我们的中心假设是，细胞-细胞黏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细胞的动态平衡。我们的长期目标分为两大主题，以应对以下关键挑战：a.涉及钙粘附素介导的细胞-细胞黏附、细胞骨架组织和细胞迁移调节的机制；以及b.细胞-细胞黏附复合体对机械应变扰动的反应。基于之前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-细胞黏附过程中αE-连环蛋白(A.1)和肌动蛋白(A.2)动态的调节，以及控制细胞-细胞黏附和迁移之间平衡的钙粘附素和整合素黏附之间的串扰(A.3)；和主题B。在机械应变和细胞周期重新进入时，β-连环蛋白和YAP1如何转位到细胞核(B.1)，肌球蛋白活性(B.2)和激酶(B3)在激活β-连环蛋白中的作用 和YAP1，以及额外的连接介导的信号通路参与细胞周期调节(B.4)。这些研究的完成将回答关于细胞-细胞黏附在细胞骨架组织和细胞迁移中的作用，以及隔离调节细胞增殖的关键信号蛋白的关键问题。这些研究解决了在理解正常和疾病状态下的上皮组织组织调节方面的基本挑战。

 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.