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.

项目总结/摘要 上皮细胞的集体迁移在形态发生、肠更新、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。对于上皮层来说， 然而，在迁移过程中，这种机制必须在整个组织平面上全局对齐。确定这是如何 实现组织级极化是集体迁移场的中心目标。我们研究一种旋转形式 当组织被限制在圆形或球形几何形状时发生的上皮迁移。旋转 迁移在两个方面不同于其它上皮迁移。首先，外部线索，如空的空间或化疗- 战术信号不能用于引导组织极化。相反，细胞必须完全依赖于本地细胞-细胞 为了达到这种状态，相互作用。细胞如何自我组织旋转迁移是未知的。二是 没有净组织运动，这就提出了为什么会发生这些迁移的问题。轮换促进了 排列在组织基底表面的基底膜细胞外基质的组装;它甚至可以 形成高度结构化的基底膜，指导器官的形态发生。如何旋转 对基底膜组装的影响知之甚少。值得注意的是，最近的研究表明，上皮细胞 旋转可能有助于人类器官的发育，因为乳房类器官的球形肺泡随着旋转而旋转。 尽管它们连接到中央管道系统， 我的NIGMS资助的研究有两个目标：（1）确定局部细胞间的相互作用， 自组织的旋转迁移，（2）以确定如何旋转结构的基底膜。 为此，我们正在研究一个旋转迁移，发生在滤泡上皮的果蝇。在 近年来，我们使用这个模型，以提供第一次深入了解局部细胞间的相互作用， 上皮细胞的旋转迁移，通过确定一个新的平面信号系统，介导这一过程。我们 还表明，旋转与新的蛋白质分泌，以创造纤维在基底膜， 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毛囊细胞打破对称性并启动迁移， 信号传导在分子水平上起作用--无论是蛋白质之间的相互作用，还是蛋白质与蛋白质之间的相互作用。 移徙机制。我们还将探讨两种机制，其中机械力赋予旋转 迁移可能影响基底膜组装。这项工作将揭示新的指导原则， 组织水平的有序是如何从局部细胞间的相互作用中产生的。此外，由于基底膜 是大多数器官的核心，它们的组装缺陷是肌肉萎缩症、肾病、皮肤病 水泡和中风，我们对这个知之甚少的过程的任何了解都将产生广泛的影响。