Effect of CFTR Modulators on Chloride Homeostasis and Excitability in Sensory Neurons from CFTR F508del Mice
Date
2025-05-28
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
ORCID
0009-0003-7934-0031
Type
Thesis
Degree Level
Masters
Abstract
Cystic Fibrosis (CF) is an autosomal recessive disorder resulting from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The F508del mutation represents the most prevalent variant, affecting approximately 80% of patients. While advancements in medical technologies have significantly extended life expectancy, many adult people with CF (pwCF) now experience long-term complications, including peripheral neuropathy. Previous findings from the Campanucci lab demonstrated disrupted chloride homeostasis and reduced excitability in dorsal root ganglion (DRG) neurons from CFTR-/- swine. To further bridge these findings to human relevance, this study analyzed chloride homeostasis and neuronal excitability in DRG neurons from mice carrying the F508del mutation and assessed the effect of the CFTR modulator Elexacaftor/Tezacaftor/Ivacaftor (ETI). Chloride imaging with MQAE (N-Ethoxycarbonylmethyl-6-Methoxyquinolinium Bromide) dye revealed impaired chloride homeostasis in F508del DRG neurons, which ETI failed to correct. Voltage-clamp electrophysiology showed increased action potential (AP) generation in DRG neurons from both male and female mice carrying the F508del mutation and following ETI treatment. However, further investigation into T-type calcium channel (Cav 3.2) functionality revealed no significant effect of the F508del mutation or ETI treatment on activity. These findings suggest that the F508del mutation and ETI’s influence on neuronal excitability do not extend to voltage-gated calcium (Cav) channels, implying that other mechanisms of peripheral neuropathy are associated with CF. This study highlights the contrasting tissue-specific effects of ETI therapy and calls attention to the need for further research into its limited effectiveness in nervous tissues.
Description
Keywords
Cystic Fibrosis
Neuropathic
CFTR
ETI
Modulators
Citation
Degree
Master of Science (M.Sc.)
Department
Anatomy, Physiology, and Pharmacology
Program
Anatomy, Physiology, and Pharmacology