Advisory Committee Chair
Steven Rowe
Advisory Committee Members
Jarrod Barnes
Document Type
Dissertation
Date of Award
2024
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Cystic fibrosis (CF) is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a channel responsible for the transport of chloride and bicarbonate ions across the apical cell surface. In the respiratory tract, defective CFTR results in viscous and adherent mucus that becomes static within the airway, which leads to chronic infections, progressive lung damage, and early mortality. Historically, CF mucus stasis has been attributed to significant airway dehydration; however, growing evidence has demonstrated that aberrant electrostatic properties of mucins also contribute to mucus stasis in CF. Mucins are large, polymeric glycoproteins that provide the structure of the mucus gel and govern its rheological properties. Extensive hydroxyl (O)-linked glycosylation of mucins greatly contributes to their gel forming properties. These glycans are largely terminated by sialic acids, which impart mucins with strong negative charges that are important for their electrostatic characteristics and interactions with the ionic environment. Previous work has highlighted the consequences of the altered CF ionic environment on mucin maturation and mucus clearance; however, the roles of intrinsic mucin charge on the biophysical properties of mucin and MCC have not been fully elucidated. In this work, we develop a novel model to study mucus pathology in the CF airway and demonstrate its utility to better understand submucosal gland dysfunction. Furthermore, we utilize a polycationic polymer, SNSP113, to therapeutically target mucin charge abnormalities, and show that it improves mucus transport and lung pathology in the Scnn1b-Tg mouse model, extending its efficacy to correct the electrostatic properties of mucus in diseases beyond CF. Next, we demonstrate the consequences of reduced mucin sialylation on mucin charge, expansion, and mucociliary clearance, providing novel insights into the role of mucin charge in facilitating normal mucus properties. Finally, we identify decreased sialyltransferase expression in CF human bronchial epithelial cells that is potentially linked to defective CFTR. Altogether, this work demonstrates the importance of the electrostatic relationship between negatively charged mucin and airway cations in the processes of mucin expansion and mucociliary clearance. This work also provides impetus to further investigate mucin sialylation/charge as a potential therapeutic target to treat mucus stasis in CF and potentially other muco-obstructive diseases.
Recommended Citation
Rose, Elex Skylar, "Investigating The Electrostatics Of Mucins As Key Contributors To Mucus Stasis In Cystic Fibrosis" (2024). All ETDs from UAB. 3839.
https://digitalcommons.library.uab.edu/etd-collection/3839