Mechanisms of epithelial migration and basement membrane assembly

上皮迁移和基底膜组装的机制

• 批准号: 10552458
• 负责人: Sally Horne-Badovinac
• 金额: $ 59.38万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10552458
• 关键词: Alveolus; Basement membrane; Bulla; Cell Communication; Cells; Cues; Defect; Drosophila genus; Epithelial Cells; Epithelium; Extracellular Matrix; Extracellular Structure; Funding; Genetic; Geometry; Goals; Human; Individual; Intestines; Kidney Diseases; Learning; Mediating; Modeling; Molecular; Morphogenesis; Movement; Muscular Dystrophies; National Institute of General Medical Sciences; Neoplasm Metastasis; Organ; Organoids; Play; Process; Protein Secretion; Proteins; Research; Role; Rotation; Shapes; Signal Transduction; Skin; Stroke; Structure; Surface; System; Tissues; Work; cell motility; insight; mammary; mechanical force; membrane assembly; migration; novel; organ growth; programs; self organization; wound healing

PROJECT SUMMARY / ABSTRACT Collective migration of epithelial cells plays central roles in morphogenesis, intestinal turnover, wound repair, and metastasis. Epithelial cells use the same migration machinery as individual cells. For an epithelial sheet to migrate, however, this machinery must become globally aligned across the tissue plane. Determining how this tissue-level polarization is achieved is a central goal of the collective migration field. We study a rotational form of epithelial migration that occurs when the tissue is confined to a circular or spherical geometry. Rotational migrations differ from other epithelial migrations in two ways. First, external cues like empty space or chemo- tactic signals are not available to guide tissue polarization. Instead, the cells must rely solely on local cell-cell interactions to achieve this state. How cells self-organize for rotational migration is unknown. Second, there is no net tissue movement, which raises the question of why these migrations occur. Rotation promotes the assembly of the basement membrane extracellular matrix that lines the tissue’s basal surface; it can even create highly structured basement membranes that direct organ morphogenesis. However, how rotation impacts basement membrane assembly is poorly understood. Notably, recent work has shown that epithelial rotation may contribute to human organ development, as the spherical alveoli of mammary organoids rotate as they form despite being connected to a central ductwork. My NIGMS-funded research has two goals: (1) to define the local cell-cell interactions that allow epithelial cells self-organize for rotational migration, and (2) to determine how rotation structures the basement membrane. To this end, we are studying a rotational migration that occurs in the follicular epithelium of the Drosophila. In recent years, we used this model to provide the first insight into the local cell-cell interactions that polarize an epithelium for rotational migration by identifying a novel planar signaling system that mediates this process. We also showed that rotation works with new protein secretion to create fibrils in the basement membrane that control tissue shape. Through the MIRA program, we will dig deeper into both mechanisms. We will determine how the planar signaling system allows the follicle cells to break symmetry and initiate migration and how the signaling works at molecular level - both in terms of how the proteins interact with one another and with the migration machinery. We will also explore two mechanisms by which mechanical forces imparted by rotational migration are likely to influence basement membrane assembly. This work will reveal new guiding principles for how tissue-level order can emerge from local cell-cell interactions. Moreover, because basement membranes are central to most organs and defects in their assembly underly muscular dystrophy, nephropathy, skin blistering, and stroke, anything we learn about this poorly understood process will have broad impact.

项目摘要 /摘要 上皮细胞的集体迁移在形态发生，肠道更换，伤口修复， 和转移。上皮细胞使用与单个细胞相同的迁移机制。对于上皮床单 但是，迁移，这种机械必须在整个组织平面上进行全局排列。确定如何 实现组织级极化是集体迁移场的核心目标。我们研究旋转形式 当组织局限于圆形或球形几何形状时发生的上皮迁移。旋转 迁移与其他上皮迁移不同。首先，外部提示，例如空空间或化学疗法 战术信号无法指导组织极化。相反，细胞必须仅依靠局部细胞细胞 互动以实现这一状态。细胞如何进行旋转迁移的自组织是未知的。第二，有 没有净组织运动，这提出了为什么发生这些迁移的问题。旋转促进 地下膜的细胞外基质的组装，该基质将组织的基本表面排成；它甚至可以 创建高度结构化的地下机制，可导致器官形态发生。但是，如何旋转 影响地下膜组件的影响很少。值得注意的是，最近的工作表明上皮 旋转可能有助于人类生物的发育，因为乳腺癌的球形肺泡旋转为 尽管它们与中央管道连接在一起，但它们还是形成了。 我的NIGMS资助的研究有两个目标：（1）定义允许上皮细胞的局部细胞相互作用 自组织以进行旋转迁移，（2）确定旋转如何结构地下膜。 为此，我们正在研究果蝇卵泡上皮中发生的旋转迁移。在 近年来，我们使用该模型为局部细胞 - 细胞相互作用提供了首次见解，以极化 通过识别介导该过程的新型平面信号传导系统，用于旋转迁移的上皮。我们 还表明，旋转与新的蛋白质分泌作用，在地下膜中创建原纤维， 控制组织形状。通过MIRA计划，我们将深入研究这两种机制。我们将确定 平面信号系统如何允许植物细胞打破对称性并启动迁移以及如何 信号传导在分子水平上起作用 - 既有蛋白质如何相互相互作用，并且与 迁移机械。我们还将探索两种机制，由旋转赋予的机械力 迁移可能会影响基底膜组装。这项工作将揭示新的指导原则 组织水平的顺序如何从局部细胞 - 细胞相互作用中出现。而且，因为地下室机制 对于大多数器官和在肌肉营养不良，肾病，皮肤下的组装中的缺陷都是核心 泡沫和中风，我们了解的任何知识不足的过程都会产生广泛的影响。