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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL034030-03
Application #
3346559
Study Section
Pathology A Study Section (PTHA)
Project Start
1985-06-01
Project End
1989-05-31
Budget Start
1987-06-01
Budget End
1989-05-31
Support Year
3
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Tennessee Knoxville
Department
Type
Schools of Veterinary Medicine
DUNS #
City
Knoxville
State
TN
Country
United States
Zip Code
37996
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Maddux, J M; Edwards, D F; Barnhill, M A et al. (1991) Neutrophil function in dogs with congenital ciliary dyskinesia. Vet Pathol 28:347-53
Edwards, D F; Kennedy, J R; Toal, R L et al. (1989) Kartagener's syndrome in a chow chow dog with normal ciliary ultrastructure. Vet Pathol 26:338-40
Edwards, D F; Kennedy, J R; Patton, C S et al. (1989) Familial immotile-cilia syndrome in English springer spaniel dogs. Am J Med Genet 33:290-8
Kennedy, J R; Dunlap, J R; Bunn, R D et al. (1988) Utilization of digital image processing to study dynein arms (ATPase) in normal and immotile cilia. J Electron Microsc Tech 8:159-72