Mechanotransduction in morphogenesis of mucociliary epithelium and multiciliated cells

粘液纤毛上皮和多纤毛细胞形态发生中的机械转导

• 批准号: 10705235
• 负责人: Saurabh S Kulkarni
• 金额: $ 40.38万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705235
• 关键词: Affect; Apical; Architecture; Area; Biomechanics; Breathing; Calibration; Cells; Centrioles; Cilia; Defect; Development; Embryo; Epithelium; Genes; Goals; Impairment; Individual; Inhalation; Ion Channel; Lung; Mechanics; Molecular; Morphogenesis; Mucociliary Clearance; Mucous body substance; Organelles; Outcome; Pathologic; Pathway interactions; Piezo 1 ion channel; Play; Process; Property; Research; Respiratory Disease; Role; System; Time; Tissues; Toxin; Work; Xenopus; fluid flow; in vivo Model; mechanical force; mechanotransduction; pathogen; prevent

Abstract Every time we breathe, we inhale toxins and pathogens. The mucus produced in our airway traps these pathogens. Thousands of multiciliated cells (multiple cilia per cell, MCCs) line the epithelium of our airway work in a synchronized fashion to propel the mucus upwards and out of our body. This coordinated process is known as mucociliary clearance, which prevents pathogens from moving to our lungs and causing irreparable damage. Despite the central role MCCs play in mucociliary clearance, our understanding of the morphogenesis of MCCs in the context of mucociliary epithelium remains incomplete. For example, the assembly of too many or too few cilia is associated with impaired MCC function and can lead to pathological outcomes. However, the mechanisms that define the cilia number remain unaddressed. Using an in vivo model of Xenopus embryonic epidermal MCCs, we recently discovered that the centriole number depends on the apical area of the cell. Moreover, we demonstrated that mechanical tension that affects the apical area of MCCs also calibrates centriole number via mechanosensitive (MS) ion channel Piezo1. Our results have raised many important questions about the mechanisms of Piezo1 function in MCCs. Also, they strongly suggested that mechanotransduction plays a central role in the morphogenesis of mucociliary epithelia, specifically MCCs. This proposal will focus on elucidating the role of mechanical forces and mechanotransduction pathways in determining the centriole number and apical area of MCCs and non-MCCs using three complementary approaches. First, we will take a gene-specific approach to examine the role of Piezo1 in centriole number control. Second, we will take a cellular biomechanics approach to understand the interaction between tissue- scale and cell-intrinsic forces in determining the apical area of MCCs and non-MCCs. Third, we will use a systems approach to identify other MS genes involved in MCC morphogenesis. Our long-term goal is to elucidate the mechanisms that define the properties of individual organelles (e.g., size and number of cilia) and how they relate to the architecture of cells (e.g., apical size, cilia organization) and the mucociliary tissue (arrangement of MCCs and non-MCCs) to generate efficient fluid flow.

抽象的 每次我们呼吸时，我们都会吸入毒素和病原体。我们气道中产生的粘液会捕获这些 病原体。数千个多纤毛细胞（每个细胞有多个纤毛，MCC）排列在我们气道的上皮细胞上 以同步的方式将粘液向上推动并排出我们的身体。这个协调的过程是 称为粘液纤毛清除，可防止病原体移动到我们的肺部并造成不可挽回的后果 损害。尽管 MCC 在粘膜纤毛清除中发挥核心作用，但我们对形态发生的理解 粘液纤毛上皮背景下的 MCC 的研究仍然不完整。例如，组装太多 纤毛过少与 MCC 功能受损有关，并可能导致病理结果。然而， 定义纤毛数量的机制仍未得到解决。使用非洲爪蟾胚胎体内模型 在表皮MCC中，我们最近发现中心粒数量取决于细胞的顶端面积。 此外，我们证明影响 MCC 顶端区域的机械张力也会校准 通过机械敏感 (MS) 离子通道 Piezo1 的中心粒数。我们的研究结果提出了许多重要的 有关 MCC 中 Piezo1 功能机制的问题。此外，他们还强烈建议 机械转导在粘液纤毛上皮，特别是 MCC 的形态发生中起着核心作用。 该提案将重点阐明机械力和机械传导途径在 使用三个互补确定 MCC 和非 MCC 的中心粒数量和顶端面积 接近。首先，我们将采用基因特异性方法来检查 Piezo1 在中心粒数量中的作用 控制。其次，我们将采用细胞生物力学方法来了解组织之间的相互作用 规模和细胞内在力决定 MCC 和非 MCC 的顶端面积。第三，我们将使用一个 系统方法来识别参与 MCC 形态发生的其他 MS 基因。我们的长期目标是 阐明定义单个细胞器特性的机制（例如纤毛的大小和数量）以及 它们与细胞结构（例如顶端大小、纤毛组织）和粘液纤毛组织的关系 （MCC 和非 MCC 的排列）以产生有效的流体流动。