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 每当我们呼吸时，我们都会吸入毒素和病原体。气道陷阱中产生的粘液 病原体。数以千计的多毛细胞（每个细胞多个纤毛，MCC）在我们的气道工作的上皮上 以同步的方式将粘液向上和从我们体内推动。这个协调的过程是 被称为粘膜钙清除率，可防止病原体移动到我们的肺部并导致无法弥补 损害。尽管MCC在粘膜缩减清除率中起着核心作用，但我们对形态发生的理解 在粘膜上皮的背景下，MCC仍然不完整。例如，组装太多 或太少的纤毛与MCC功能受损有关，并可能导致病理学结果。但是， 定义纤毛数量的机制仍然没有解决。使用Xenopus Embryonic的体内模型 表皮MCC，我们最近发现中心数取决于细胞的顶端区域。 此外，我们证明了影响MCC顶端区域的机械张力也可以校准 通过机械敏感（MS）离子通道压电1的中心数。我们的结果提出了许多重要的 关于压电1在MCC中功能的机制的问题。另外，他们强烈建议 机械转导在粘膜上皮（特别是MCC）的形态发生中起着核心作用。 该提案将着重于阐明机械力和机械转移途径在 使用三个补充的MCC和非MCC的中心数和顶端区域 方法。首先，我们将采用一种基因特异性方法来检查压电1在中心数中的作用 控制。其次，我们将采用一种细胞生物力学方法来了解组织之间的相互作用 在确定MCC和非MCC的顶端区域时，尺度和细胞中性力。第三，我们将使用 系统方法鉴定其他与MCC形态发生有关的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）和 它们与细胞结构（例如顶端大小，纤毛组织）和粘膜组织的结构如何相关 （MCC和非MCC的排列）以产生有效的流体流动。