During the past two years it has become increasingly clear that cystic fibrosis is a disease which expresses fundamental defects in both fluid absorptive and fluid secretory transport process. There is also convincing evidence that abnormalities in both processes involve abnormally low Cl-permeability in the affected epithelia. There are strong suggestions that in secretory epithelia the failure of Cl-permeability in CF secretion may be more of a malfunction in regulation of the permeability pathway than of a defect in the """"""""structure"""""""" of the pathway itself. The defective step in regulation is not known, nor is the normal mechanism of regulating Cl-permeability. Neither is it known if Cl- permeability in the absorptive transport process is regulated at all. Hence, it is the purpose of this proposal to define the components of electrolyte absorptive transport and the components of electrolyte secretory transport in such a way that we will be able to identify the defective component common to the failure of both processes in CF. The identification of this component, or event, should make it possible to explain and perhaps intervene in the progression of pathologies expressed by critical target organs in this disease. Toward this end, we believe the human eccrine sweat gland is an almost ideal experimental preparation. The predominant functions of the gland are fluid secretion in one part and fluid absorption in the other. Both fluid secretion and fluid absorption are characteristically altered in the CF sweat gland. In contrast to normal glands, fluid secretion cannot be stimulated by beta- adrenergic agonists (Sato and Sato, 1984), and also in contrast to normal glands, absorption is markedly decreased due to a relative impermeability to Cl-(Quinton, 1983), in CF sweat glands. In this proposal, we will continue our work on this organ and on primary cultures from it, using electrophysiological techniques combined with morphological, pharmacological, and biochemical approaches to identify the common functions in both structures of the sweat gland. We expect that identification of the defect common to these two reversed transport processes in the sweat gland will lead us directly to the defect common to all target tissues affected in the disease.
