CELLULAR REGULATION OF RESPIRATORY CILIA

粘液纤毛清除功能受损可由以下两种原因引起 吸入刺激物或抗原，或在囊性等慢性疾病中发现 纤维化、哮喘和支气管炎。慢性损害影响约17 美国有数百万人，急性发作的人数要多出许多倍。 需要有效地调节粘液纤毛运输以维持 呼吸道通畅。预防吸入性呼吸道疾病 侮辱依赖于神经的完整性，内部和内部的 纤毛搏动频率、CBF和轴向的细胞调节机制 亚时波速，MWV/a；这两个参数对 粘液运输的有效性。 该项目建议研究肾上腺素能、胆碱能和 嘌呤能激动剂与下丘脑的管腔和基底外侧相互作用 用于描绘潜在的细胞内和细胞间通路的细胞 独立监管CBF和MWV/a。至少有四个主要 调节CBF刺激的受体启动的通路。其中两个 它们可以在基侧膜上被激活；腺苷环化酶 -cAMP依赖和磷脂酶C-肌醇磷酸(IP3) 依赖途径。两个可以从气道腔被激活 (可能在纤毛上)；依赖鸟苷环化酶-cGMP和 磷脂酶C-肌醇磷酸(IP3)依赖途径。每一个 这些通路与钙激活的钾通道相连，该通道 通畅是刺激脑血流的必要前提。只有一位 这些途径是底侧腺苷环化酶依赖的cAMP途径 导致细胞内cAMP增加和伴随而来的 MWV/a。两种体外检测，即CBF和MWV/a，将从 一种新开发的双光束激光散射系统。 通过描述这些职能的控制机制，它将是 从长远来看，可能建立独立和集体的 CBF和MWV/a在粘液纤毛转运中的作用这将是第一次 在体外进行研究，并在体内确认为可用的技术。 细胞内和细胞内纤毛调控通路的研究 函数是理解 粘液纤毛系统对吸入刺激物和内源性炎症的影响 并且是确定功能异常的先决条件 由毒素或疾病引起的。无论是药物还是分子 预防或治疗干预的方法被开发出来。 取决于异常的细胞和分子基础 该项目将为今后的工作提供方向和基础 学习。

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.