PATHOPHYSIOLOGY OF IMMOTILE CILIA SYNDROME: A MODEL

人和狗的不活动纤毛综合征(ICS)是一种遗传病 以睫毛功能障碍为特征的。临床表现与纤毛有关 器官和细胞的运动性。粘液纤毛清除缺失导致复发 呼吸道感染，是慢性阻塞性肺病的原因之一。 男性不育，白细胞运动缺陷，可能还有脑积水 是这种疾病的附加特征。 一种独特的人类ICS犬模型的研究将用于实现 明确的目标。这些目标将是：1)描述和量化 ICS的超微结构和功能损害 呼吸道纤毛，并确定慢性支气管炎是否有 与这些损害的因果关系。这些研究产生的数据 将与患有ICS和其他疾病的人类可用的 影响呼吸道纤毛的疾病。这将通过以下方式实现 多个活检组织的电子显微镜和光谱分析 培养的纤毛外植体。治疗后呼吸道纤毛的评价 VS未经处理的ICS犬、气溶胶感染的SPF犬和感染的外植体 培养将被用来阐明细菌在生产过程中的作用 ICS纤毛的形态和功能损害。2)确定 ICS中可能存在影响纤毛的循环抑制物 功能和细胞运动性。涉及中性粒细胞趋化的研究 (微孔过滤技术)、精子活力和纤毛搏动 (光谱分析)将用来检验这一假说。3)至 睫状体结构和功能缺陷与持续时间的关系 获得性肺病理疾病(形态和形态计量学 分析)和在其他纤毛器官中发现的病理(如脑积水， 中耳炎、鼻窦炎、不孕症和内翻症)。4)定义 遗传模式。 这项建议的长期目标旨在扩大 介绍有关ICS的病理生理学基础的知识，并确定 诊断的绝对标准和与之分离或包括在内， 其他先天性睫状体功能障碍(杨氏综合征) 天哪。此外，通过表征相关疾病的谱系 对于ICS(脑积水，男性不育)，这些研究应该会给出新的 洞察并促使对这些疾病的发病机制进行新的研究 人类的疾病。在这方面，这种动物模型的发展 将被用作其他调查人员的资源。

Immotile cilia syndrome (ICS) in man and the dog is a genetic disease characterized by ciliary dysfunction. Clinical findings relate to ciliated organs and cell motility. Absent mucociliary clearance leads to recurrent respiratory infections and is a cause of chronic obstructive lung disease. Male infertility, defective leukocyte movement and possibly hydrocephalus are additional features of this disorder. Investigation of a unique canine model of human ICS will be used to achieve specific aims. These aims will be: 1) to characterize and quantify the ultrastructural and functional lesions of ICS that are present in respiratory cilia, and to determine if chronic bronchial infections have a causal relationship with these lesions. Data generated from these studies will be compared with that available for humans with both ICS and other diseases affecting respiratory cilia. This will be accomplished by electron microscopic and optical spectrum analysis of multiple biopsies and cultured ciliated explants. Evaluation of respiratory cilia from treated vs nontreated ICS dogs, aerosol infected SPF dogs and infected explant cultures will be used to clarify the role of bacteria in producing morphologic and functional lesions of cilia in ICS. 2) to determine the potential presence of a circulating inhibitor in ICS which affects ciliary function and cell motility. Studies involving neutrophil chemotaxis (micropore filter technique), spermatozoal motility, and ciliary beat (optical spectrum analysis) will be used to test this hypothesis. 3) to correlate defects of ciliary structure and function, and duration of disease with acquired pulmonary pathology (morphologic and morphometric analysis) and pathology found in other ciliated organs (eg, hydrocephalus, otitis media, sinusitis, infertility and situs inversus). 4) to define the pattern of inheritance. The long term objectives of this proposal are designed to expand the present knowledge regarding the pathophysiologic basis of ICS, and identify absolute criteria for its diagnosis and separation from, or inclusion with, other congenital disorders of ciliary dysfunction (Young's syndrome) of man. Additionally by characterizing the spectrum of disorders associated with ICS (hydrocephalus, male infertility), these studies should give new insight and prompt new investigations into the pathogenesis of these disorders in the human. In this regard, development of this animal model will be used as a resource for other investigators.