PATHOPHYSIOLOGY OF IMMOTILE CILIA SYNDROME: A MODEL

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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.