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MECHANISM OF BICARBONATE SECRETION ACROSS THE TRACHEAL EPITHELIUM: ABERRANT REGULATION BY CFTR

Wheat, Valerie Jo
http://rave.ohiolink.edu/etdc/view?acc_num=ucin998078909

Abstract Details

2001, PhD, University of Cincinnati, Medicine : Pathobiology and Molecular Medicine.
Cystic Fibrosis is the most common lethal inherited disease in the Caucasian population. It is caused by autosomal recessive inheritance of mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). Although CFTR is a chloride channel, the disease process of CF seems to involve not only defective chloride secretion, but defective bicarbonate secretion as well. The purpose of these studies was to determine the mechanism of bicarbonate secretion in the trachea, and to explore its regulation by CFTR. These studies utilize a tissue culture model system of CFT-1 cells derived from a patient with the homozygous ΔF508 mutation in CFTR, and CFT-1 cells retrovirally infected with functional CFTR (CFT-WT cells). Functional presence of a Cl - /HCO 3 - exchanger is shown, with decreased activity in CFT-1 cells. This decreased activity is attributed to absence of expression of the apical Cl - /HCO 3 - exchanger DRA/CLD. To confirm the role of CFTR in inducing DRA expression, adenoviral infection of the CFT-1 cells with wild-type CFTR was performed. In the monolayers infected with Ad-CFTR (20 pfu/cell) for 24, 48, and 72 hours, DRA expression was detected. Control cells did not show DRA expression, nor did the monolayers infected for 7 days. These studies demonstrate the absence of CFTR expression, as in the CF cells, causes absence of expression of DRA, an apical Cl - /HCO 3 - exchanger. This lack of DRA expression could account for a portion of the bicarbonate secretion defect in CF. Next, the basolateral uptake and accumulation of bicarbonate within the cell was examined. These studies identify the Na+/H+ exchanger (NHE) and Na + :HCO 3 - cotransporter (NBC) isoforms expressed in tracheal epithelial cells. Tracheal epithelial cells express the NHE-1 isoform, and exhibit the presence of functional Na+/H+ exchanger with properties consistent with the classical NHE. NHE functional activity is inhibited by the addition of amiloride. These cell lines express four NBC isoforms, and NBC-2 and NBC-3 isoforms show increased expression in the presence of functional CFTR. Both cell lines show Na+-dependent HCO 3 - uptake that is sensitive to DIDS, characteristic of NBC functional activity. These studies demonstrate that CFTR expression can also regulate expression of other acid-base transporters, and that aberrant regulation of transporter isoform expression by CFTR may contribute to the bicarbonate secretion defect of CF. The mechanism of CFTR expression affecting expression of other acid-base transporters is hypothetical, and will involve further investigation.
Manoocher Soleimani (Advisor)
CFTR; BICARBONATE SECRETION; SODIUM-BICARBONATE COTRANSPORTER; CYSTIC FIBROSIS

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Citations

  • Wheat, V. J. (2001). MECHANISM OF BICARBONATE SECRETION ACROSS THE TRACHEAL EPITHELIUM: ABERRANT REGULATION BY CFTR [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin998078909

    APA Style (7th edition)

  • Wheat, Valerie. MECHANISM OF BICARBONATE SECRETION ACROSS THE TRACHEAL EPITHELIUM: ABERRANT REGULATION BY CFTR. 2001. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin998078909.

    MLA Style (8th edition)

  • Wheat, Valerie. "MECHANISM OF BICARBONATE SECRETION ACROSS THE TRACHEAL EPITHELIUM: ABERRANT REGULATION BY CFTR." Doctoral dissertation, University of Cincinnati, 2001. http://rave.ohiolink.edu/etdc/view?acc_num=ucin998078909

    Chicago Manual of Style (17th edition)

ucin998078909
© 2001, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.