PATHOPHYSIOLOGY OF IMMOTILE CILIA SYNDROME: A MODEL

不动纤毛综合征（ICS）是一种遗传性疾病 以纤毛功能障碍为特征。 临床结果与纤毛相关 器官和细胞运动。 缺乏粘膜纤毛清除导致复发性 呼吸道感染，是慢性阻塞性肺病的一个原因。 男性不育，白细胞运动缺陷和可能的脑积水 是这种疾病的附加特征 研究人类ICS的独特犬模型将用于实现 具体目标。 这些目标将是：1）表征和量化 ICS的超微结构和功能性病变，存在于 呼吸道纤毛，并确定慢性支气管感染是否有 与这些病变的因果关系。 这些研究产生的数据 将与ICS和其他 影响呼吸纤毛的疾病。 这将通过 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 与未给药ICS犬、气溶胶感染SPF犬和感染外植体相比 培养将被用来澄清细菌在生产中的作用， ICS中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剂 功能和细胞运动性。 中性粒细胞趋化性研究 （精滤器技术）、精子活力和纤毛搏动 （光谱分析）将被用来测试这一假设。 3)到 睫状体结构和功能的相关缺陷，以及 获得性肺病理学（形态学和形态测量学）疾病 分析）和在其它纤毛器官中发现的病理学（例如，脑积水， 中耳炎、鼻窦炎、不孕症和内脏逆位）。 4)来定义 继承的模式。 本提案的长期目标旨在扩大 介绍有关ICS病理生理基础的知识，并确定 其诊断和分离的绝对标准，或与， 其他先天性睫状体功能障碍（杨氏综合征） 伙计 此外，通过表征与癌症相关的疾病谱， ICS（脑积水，男性不育），这些研究应该给新的 洞察力和及时的新调查的发病机制，这些 人类的疾病。 在这方面，这种动物模型的开发 将被用作其他研究人员的资源。

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.