The regulation of airway ciliary activity

气道纤毛活动的调节

• 批准号: 6603333
• 负责人: MICHAEL J. SANDERSON
• 金额: $ 31.8万
• 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/6603333
• 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）：粘纤毛清除是防止异物在气道中积累并依赖合作睫状活动的主要肺防御机制。 在气道上皮细胞中，Ca2+通常用作细胞调节的信号，并强烈影响睫状节频率（CBF）。 但是，我们对CA2+对气道睫状活性的调节和协调的理解非常差，尽管这对于我们对阻塞性肺部疾病中气道上皮的生理学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，但是气道细胞中CA2+振荡和波的基础机制，它们相互相互作用，并且每个彼此的相互作用几乎都不清楚。 细胞外ATP刺激CA2+振荡，并且气道上皮细胞中CBF的增加。 这非常重要，因为ATP（或UTP）由气道上皮释放，并且可以作为粘膜胶体运输的局部调节剂。但是，ATP释放的机理尚不清楚。 因此，我们的假设是CA2+振荡在单个细胞内提供时间空间上的Ca2+梯度，以调节和协调睫状活性，从而控制粘膜纤毛清除率。 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粘毛运输。通过了解CA2+信号如何控制和协调睫状活性以及细胞内的细胞内振荡如何在细胞内发生，这项研究将显着有助于我们对气道防御机制的病理生理学的了解和理解，CA2+信号转导的原理，在不可能的细胞中的原理以及ATP或UTP作为预防性疾病的潜在使用。