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.

摘要 我们每次呼吸，都会吸入毒素和病原体。在我们的呼吸道产生的粘液捕获这些 病原体成千上万的多纤毛细胞（每细胞多纤毛，MCC）排列在我们的气道上皮细胞中 以同步的方式将粘液向上排出体外。这一协调过程是 被称为粘膜纤毛清除，它可以防止病原体移动到我们的肺部，并造成不可挽回的 损害尽管MCCs在粘膜纤毛清除中起着中心作用，但我们对MCCs形态发生的理解， MCCs在粘膜纤毛上皮的背景下仍然不完整。例如，组装太多 或纤毛过少与MCC功能受损相关，并可导致病理结果。但 定义纤毛数量的机制仍然没有解决。使用非洲爪蟾胚胎的体内模型 在表皮MCCs中，我们最近发现中心粒的数量取决于细胞的顶端区域。 此外，我们证明了影响MCCs顶面的机械张力也会校准 通过机械敏感（MS）离子通道Piezo 1的中心粒数。我们的研究结果提出了许多重要的 Piezo 1在MCCs中的作用机制问题。此外，他们强烈建议， 机械转导在粘膜纤毛上皮细胞，特别是MCC的形态发生中起着中心作用。 这项建议将集中在阐明机械力和机械转导途径在 用三种互补的方法测定MCC和非MCC的中心粒数和顶面积， 接近。首先，我们将采取基因特异性的方法来研究Piezo 1在中心粒数中的作用 控制其次，我们将采用细胞生物力学方法来理解组织之间的相互作用- 尺度和细胞内力在确定MCCs和非MCCs的顶面积。第三，我们将使用 系统的方法，以确定参与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性质的机制（例如，纤毛的大小和数量）， 它们如何与细胞的结构相关（例如，顶端大小，纤毛组织）和粘液纤毛组织 （MCC和非MCC的布置）以产生有效的流体流动。