All ETDs from UAB

Advisory Committee Chair

Steven M Rowe

Advisory Committee Members

James F Collawn

Charles O Elson

Eugenia Kharlampieva

Bradley K Yoder

Document Type

Dissertation

Date of Award

2018

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Cystic fibrosis (CF) is a genetic disease resulting from mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR is an ion channel responsible for proper movement of chloride and bicarbonate ions across the apical cell surface. Defective CFTR results in an absence of bicarbonate transport, which functions in part to chelate Ca2+, a divalent cation found in abundance in mucin granules in normal conditions; this yields a hyperviscous and adhesive mucus on the respiratory and gastrointestinal tracts of patients with CF. Bronchial mucins are glycosylated proteins with neutral and negative sugars modified by negatively charged sialic and neuraminic acids and sulfates. These mucins are the primary determinants of mucus viscosity and adhesion. Similarly, bacterial biofilms contain negatively charged polysaccharides that undergo Ca2+-dependent cross-linking of matrix material to maintain integrity. Stagnant mucus, bacterial overgrowth, persistent inflammation, and tissue destruction characterize the disease, but how the defect in CFTR function is coupled to the mucus phenotype is still controversial. PAAG, a novel therapeutic, is a polycationic derivative of polyglucosamine that is a soluble, nontoxic polysaccharide shown to interact with mucins and biofilms. Our data show that PAAG, but not the neutral polymer HPMC, improved viscosity and transport of CF sputum and altered mucin conformation from a condensed, globular form to resemble a more normal, linear form. These findings indicate the effects of PAAG on mucus viscosity are tied to altered mucin structure and are dependent on Ca2+. PAAG reduced bacterial biofilm integrity by a similar mechanism and has an effect on bacterial killing, which enhances activity of antibiotics. PAAG indicates a promising potential therapeutic for the treatment of CF and other diseases affected by abnormal mucus and recalcitrant biofilms.

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