The regulation of airway ciliary activity

气道纤毛活动的调节

• 批准号: 6522138
• 负责人: MICHAEL J. SANDERSON
• 金额: $ 36.27万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6522138
• 关键词: adenosine triphosphate; biological signal transduction; calcium flux; cilium /flagellum motility; clinical research; cystic fibrosis; human tissue; laboratory mouse; laboratory rabbit; respiratory epithelium

DESCRIPTION (provided by applicant): Mucociliary clearance is the primary lung defense mechanism that prevents the accumulation of foreign material in the airways and relies on cooperative ciliary activity. In airway epithelial cells, Ca2+ commonly serves as a signal for cell regulation and strongly influences ciliary beat frequency (CBF). However, our understanding of the regulation and coordination of airway ciliary activity by Ca2+ is extremely poor even though this is vital to our comprehension of the physiology and dysfunction of the airway epithelium in obstructive lung disease. Changes in intracellular Ca2+ concentration occur in the form of propagating intercellular Ca2+ waves or asynchronous Ca2+ oscillations. These signals can encode spatial and temporal regulatory information but the mechanisms underlying Ca2+ oscillations and waves in airway cells, their interactions with each other and the consequences each have for airway cell physiology is virtually unknown. Extracellular ATP stimulates both Ca2+ oscillations and increases in CBF in airway epithelial cells. This is extremely important because ATP (or UTP) is released by the airway epitheliurn and may serve as a local regulator of mucociliary transport. However, the mechanism of ATP release is unknown. Consequently, our hypothesis is that Ca2+ oscillations provide temporal-spatial Ca2+ gradients within individual cells to regulate and coordinate ciliary activity and thereby control mucociliary clearance. To test this hypothesis, our specific aims are 1) to determine the molecular mechanisms linking changes in Ca2+ with changes in CBF in airway epithelial cells and the route of ATP release, 2) to characterize the spatial organization of intracellular Ca2+ oscillations and their relevance to ciliary activity of airway epithelial cells and 3) to quantify the relationship between Ca2+, CBF, metachrony and the control of mucociliary transport. By understanding how Ca2+ signals control and coordinate ciliary activity and how intracellular Ca2+ oscillations occur within cells, this research will significantly contribute to our knowledge and understanding of the pathophysiology of airway defense mechanisms, the principles of Ca2+ signal transduction in non-excitable cells and the potential use of ATP or UTP as therapeutic agents for airway disease.

描述（由申请人提供）：粘膜纤毛清除是主要的肺部防御机制，可防止异物在气道中积聚，并依赖于纤毛的协同活动。 在气道上皮细胞中，Ca2+ 通常充当细胞调节信号并强烈影响纤毛跳动频率 (CBF)。 然而，我们对 Ca2+ 气道纤毛活动的调节和协调的理解极少，尽管这对于我们理解阻塞性肺病中气道上皮的生理和功能障碍至关重要。 细胞内 Ca2+ 浓度的变化以传播细胞间 Ca2+ 波或异步 Ca2+ 振荡的形式发生。 这些信号可以编码空间和时间调节信息，但气道细胞中 Ca2+ 振荡和波的机制、它们之间的相互作用以及各自对气道细胞生理学的影响实际上是未知的。 细胞外 ATP 刺激气道上皮细胞中的 Ca2+ 振荡并增加 CBF。 这是极其重要的，因为 ATP（或 UTP）是由气道上皮释放的，并且可以作为粘膜纤毛运输的局部调节剂。然而，ATP 释放的机制尚不清楚。 因此，我们的假设是 Ca2+ 振荡在单个细胞内提供时空 Ca2+ 梯度，以调节和协调纤毛活动，从而控制粘膜纤毛清除。 为了检验这一假设，我们的具体目标是 1) 确定气道上皮细胞中 Ca2+ 变化与 CBF 变化之间的分子机制以及 ATP 释放途径，2) 表征细胞内 Ca2+ 振荡的空间组织及其与气道上皮细胞的纤毛活动，3) 量化 Ca2+、CBF、异时性和粘膜纤毛运输控制之间的关系。通过了解 Ca2+ 信号如何控制和协调纤毛活动以及细胞内 Ca2+ 振荡如何在细胞内发生，这项研究将极大地有助于我们了解和理解气道防御机制的病理生理学、非兴奋性细胞中 Ca2+ 信号转导的原理以及ATP 或 UTP 作为气道疾病治疗剂的潜在用途。