Cystic fibrosis (CF), the most common semilethal hereditary disease among Caucasians, is manifest as a generalized dysfunction of exocrine glands. Mucous secretions throughout the body are abnormal in CF, but the subcellar defect underlying this abnormality is not understood. My goals are to determine first whether intestinal gylcoprotein-secreting cells of CF patients respond to extracellular secretagogues and inhibitors in the same way as do their counterparts in normal individuals, and second, whether CF mucous cells, when stimulated to secrete, carry out exocytosis in a normal fashion. Glycoprotein transport and secretion in rectal goblet and columnar cells will be studied in laboratory animals and in human rectal biopsies, both normal and CF, maintained in organ culture. The effects of various neurotransmitters, GI hormones and amines on the intracellular movement and release of radioactively labeled mucous glycoproteins will be assessed by autoradiography. The interaction, fusion and fission of intracellular membranes which accompany acceleration of exocytosis in goblet cells will be investigated in detail by freeze-fracture and electron microscopy. My freeze-fracture studies on human rectal goblet cells revealed the presence of uniquely extensive and long-lived membrane interactions in these cells. Under conditions of secretory stimulation, these interaction sites break down in an orderly sequence. Through systematic comparison of autoradiographic, freeze-fracture and ultrastructural data from normal and CF mucous cells, I hope to establish whether the CF genetic defect leads to alterations in the regulation of secretion or in the membranes involved in exocytosis.
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