CELLULAR REGULATION OF RESPIRATORY CILIA

粘膜纤毛清除功能受损可由以下因素急性诱导： 吸入刺激物或抗原，或在慢性疾病中发现，如囊性 纤维化、哮喘和支气管炎。 慢性损伤影响约17 在美国有100万人，急性发作的人数要多很多倍。 需要有效调节粘膜纤毛运输， 气道通畅 预防呼吸道疾病 损伤取决于神经间和神经内的完整性 纤毛搏动频率、CBF和轴向的细胞调节机制 异时波速度，MWV/a;负责的两个参数 粘液运输的有效性。 本项目旨在研究肾上腺素能、胆碱能和 嘌呤能激动剂与血管内皮细胞的管腔和基底外侧相互作用， 细胞描绘潜在的细胞内和细胞间通路， 独立调节CBF和MWV/a。 至少有四个主要 调节CBF刺激的受体启动途径。两 这些可以在基底外侧膜上被激活;腺苷酸环化酶 - cAMP依赖性和磷脂酶C -磷酸肌醇（IP 3） 依赖路径 两个可以从气道腔激活 （推测在纤毛上）;鸟苷酸环化酶- cGMP依赖性和 磷脂酶C -磷酸肌醇（IP 3）依赖性途径。 中的每 这些途径与钙激活钾通道偶联， 开放性是刺激CBF的必要前提。中只有一 这些途径，基底外侧腺苷酸环化酶-cAMP依赖性途径 导致细胞内cAMP增加， MWV/a。 两项体外试验，即CBF和MWV/a，将来自 一种新研制的双光束激光光散射系统。 通过描述这些功能的控制机制， 从长远来看，建立独立和集体的 CBF和MWV/a在粘液纤毛转运中的作用。 这将首先是 在体外进行了研究，并在体内进行了确认。 描述细胞间和细胞内调节纤毛运动的途径 函数对于理解 粘膜纤毛系统对吸入刺激物和内源性炎症的反应 介质，是确定功能异常的先决条件 是由毒素或疾病引起的 无论是药物还是分子 开发了用于预防或治疗干预的方法 取决于异常的细胞和分子基础， 该项目将为未来提供这样的方向和基础， 问题研究

Impairment of mucociliary clearance can be either acutely induced by inhaled irritant or antigen, or found in chronic diseases such as cystic fibrosis, asthma and bronchitis. Chronic impairment affects some 17 million people in the United States and acute episodes many times more. Effective regulation of mucociliary transport is required to maintain airway patency. Prevention of diseases in the airways from inhaled insults is dependent on the integrity of the neural, inter- and intra- cellular regulatory mechanisms for ciliary beat frequency, CBF, and axial metachronal wave velocity, MWV/a; the two parameters responsible for the effectiveness of mucus transport. This project proposes to investigate how adrenergic, cholinergic, and purinergic agonists interact with the luminal and basolateral aspects of the cell to delineate potential intra- and inter-cellular pathways that independently regulate CBF and MWV/a. There are at least four major receptor-initiated pathways that regulate the stimulation of CBF. Two of these can be activated on the basolateral membrane; an adenylate cyclase - cAMP dependent and a phospholipase C - inositol phosphate (IP3) dependent pathway. Two can be activated from the airway lumen (presumably on the cilia); a guanylate cyclase - cGMP dependent and a phospholipase C - inositol phosphate (IP3) dependent pathway. Each of these pathways is coupled to a calcium activated potassium channel whose patency is a necessary precondition for stimulation of CBF. Only one of these pathways, the basolateral adenylate cyclase-cAMP dependent pathway causes an increase in intracellular cAMP and concomitant decrease in MWV/a. Two in vitro assays, namely CBF and MWV/a, will be derived from a newly developed double beam laser light scattering system. By delineating the control mechanisms for these functions, it will be possible in the longer terms to establish the independent and collective roles of CBF and MWV/a on mucociliary transport. This will first be studied in vitro and confirmed in vivo as technology available. Delineating the inter- and intra-cellular pathways regulating ciliary function is fundamental to understanding of the response of the mucociliary system to inhaled irritants and endogenous inflammatory mediators and is a prerequisite to determine functional abnormalities caused by toxins or disease. Whether pharmaceutic or molecular approaches are developed for prophylactic or therapeutic intervention depends on the cellular and molecular basis of the abnormality in which this project will provide such direction and the basis for future studies.