Physics of bronchial epithelial unjamming

支气管上皮疏通物理学

• 批准号: 10411937
• 负责人: Jeffrey J Fredberg
• 金额: $ 55.74万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10411937
• 关键词: Adherens Junction; Air; Appearance; Back; Behavior; Biological; Biology; Carcinoma; Cell Line; Cells; Cellular biology; Complement; Data; Development; Diffusion; Disease; Duct (organ) structure; E-Cadherin; Electrical Resistance; Embryonic Development; Epithelial; Epithelial Cells; Event; Fingerprint; Foundations; Gatekeeping; Growth; Health; Human; Intervention; Lead; Liquid substance; Literature; Malignant Neoplasms; Maps; Measures; Mechanics; Mesenchymal; Molecular; Morphogenesis; Multicellular Process; N-Cadherin; Neoplasm Metastasis; Organ; PARD6A gene; Permeability; Phenotype; Physics; Physiological; Physiological Processes; Process; Route; Surface; Testing; Tight Junctions; Transitional Epithelium; Vimentin; airway remodeling; airway repair; asthmatic; asthmatic airway; attenuation; body cavity; bronchial epithelium; cell motility; combinatorial; design; epithelial repair; epithelial to mesenchymal transition; fluorescein isothiocyanate dextran; immune function; migration; multiple omics; novel; programs; protein biomarkers; protein protein interaction; slug; transcription factor; wound healing

Abstract A confluent collective of epithelial cells lines every organ surface and body cavity. The epithelial collective typically remains quiescent and non-migratory while performing its routine barrier and immune functions, but becomes dynamic and migratory during embryonic development and airway morphogenesis, during airway repair and asthmatic airway remodeling, as well as during carcinoma invasion and metastasis. In these and other processes, the striking transition between non-migratory versus migratory behaviors is traditionally framed within the context of the epithelial-to-mesenchymal transition (EMT) or the partial EMT (pEMT). During pEMT the epithelial phenotype, which is said to be innately non-migratory, transitions toward a mesenchymal phenotype, which is innately migratory. But to initiate and sustain collective cellular migration, our central hypothesis holds that the EMT/pEMT mechanism as it is canonically defined is not obligatory. Rather, we propose that the newly discovered unjamming transition (UJT) mechanism in many cases elicits collective cellular migration and, importantly, can function independently of the EMT or pEMT. Unjamming is not to be mistaken for cellular migration or for remodeling. But unjamming does create the physical conditions that make cellular migration and remodeling possible. Using the confluent layer of primary human bronchial epithelial cells (HBECs) in air-liquid-interface (ALI) culture, here we propose to: 1) establish the UJT mechanism as an independent route to collective HBEC migration; 2) map in HBECs the molecular interactome of the UJT mechanism; and 3) explain molecular, structural, and migratory features that typify the UJT mechanism. Extensive preliminary data support the tenability of these aims, which are designed to illuminate basic mechanisms that differentiate UJT from EMT.

抽象的 每个器官表面和体腔内都有上皮细胞的汇合集合。上皮细胞集体 在执行其常规屏障和免疫功能时通常保持静止和非迁移，但是 在胚胎发育和气道形态发生期间变得动态和迁移 修复和哮喘气道重塑，以及癌症侵袭和转移期间。在这些和 与其他过程一样，非迁移行为与迁移行为之间的显着转变传统上是 上皮间质转化（EMT）或部分EMT（pEMT）的背景下。期间 pEMT 上皮表型，据说是天生的非迁移性，转变为间充质 表型，即天生的迁徙性。但为了启动和维持集体细胞迁移，我们的中央 假设认为，规范定义的 EMT/pEMT 机制不是强制性的。相反，我们 提出新发现的解干扰转换（UJT）机制在许多情况下引发集体 细胞迁移，重要的是，可以独立于 EMT 或 pEMT 发挥作用。解除干扰不是必须的 被误认为细胞迁移或重塑。但解除干扰确实创造了使 细胞迁移和重塑成为可能。使用人原代支气管上皮的汇合层 气液界面（ALI）培养中的细胞（HBEC），在这里我们建议：1）建立UJT机制作为 集体 HBEC 迁移的独立途径； 2) 在 HBEC 中绘制 UJT 的分子相互作用组图 机制; 3) 解释代表 UJT 机制的分子、结构和迁移特征。 大量的初步数据支持这些目标的可行性，这些目标旨在阐明基本的 UJT 与 EMT 的区别机制。

项目成果

Airway smooth muscle tone increases actin filamentogenesis and contractile capacity.

气道平滑肌张力增加肌动蛋白丝生成和收缩能力。

• DOI: 10.1152/ajplung.00205.2019
• 发表时间: 2020
• 期刊: American journal of physiology. Lung cellular and molecular physiology
• 作者: Gazzola,Morgan;Henry,Cyndi;Lortie,Katherine;Khadangi,Fatemeh;Park,ChanYoung;Fredberg,JeffreyJ;Bossé,Ynuk
• 通讯作者: Bossé,Ynuk