The long term goal of this work is to understand the underlying error and pathophysiology of cystic fibrosis, the most common lethal genetic disease of whites. In cystic fibrosis, there are inherited abnormalities in alpha-adrenergic, beta-adrenergic and cholinergic systems. This proposal will further elucidate the biochemical bases of these abnormalities and investigate whether they contribute to the development and progression of pulmonary disease. The beta-adrenergic defect is probably at the level of receptor-cyclase coupling, so this proposal will investigate Ns (a coupling protein), phospholipid methylation, receptor desensitization, and pharmacologic modulation of receptor-cyclase coupling in leukocytes from patients with cystic fibrosis, their parents, and appropriate controls. In vitro systems will be developed to investigate the cause of increased cholinergic responses in cytic fibrosis, such as cholinergic stimulation of lysosomal enzyme release from granulocytes, or of lymphoproliferation. Changes in intracellular calcium in response to cholinergic agents will be monitored with Quin 2, and the binding properties of muscarinic receptors on lymphocytes and granulocytes will be determined. To investigate the pathophysiologic significance of these autonomic abnormalities, three strategies will be used. First, using minimally invasive tests, like the cyclic AMP response to beta agents in leukocytes and power spectral analysis of heart rate variability, this project will test autonomic function in children with cystic fibrosis prior to the onset of significant disease. Second, autonomic function will be determined in tissues affected by the cyctic fibrosis disease process using the beta-adrenergic responses of nasal biopotentials in vivo and the cyclic AMP response to beta agents in tracheocytes obtained by bronchial brushing as test systems. Third, the relation of autonomic dysfunction to airway reactivity in parents of patients with cystic fibrosis and appropriate controls will be further defined. Thus, the study will determine if autonomic dysfunction is present early in the course of the disease and if it occurs in involved tissues, and will further elucidate the relation of autonomic dysfunction and airway reactivity. Such studies have implications for the development and progression of obstructive airways disease in general, and for cystic fibrosis in particular.
Showing the most recent 10 out of 17 publications
