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New Pathways Involved in The Regulation of Epithelial Chloride Transport
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Orientador(es)
Resumo(s)
Cystic Fibrosis (CF) is an autosomal recessive disorder caused by mutations on the cystic fibrosis
transmembrane conductance regulator (CFTR) gene. The gene encodes a chloride channel (Cl-
)
expressed at the plasma membrane (PM) of epithelial cells. The deletion of phenylalanine 508
(Phe508del) is the most common mutation, it causes the protein to misfold and be prematurely
degraded, failing to reach the PM. The use of recently clinically approved CFTR modulator drugs has
changed CF management, enabling the rescue of several CFTR mutant proteins, including Phe508delCFTR folding, trafficking, and function at the PM. However, these rescued channels still exhibit
evidence of a reduced half-live at the PM, indicating space for improvement in CF therapeutic
strategies. Previous work of the host lab identified new cellular pathways and key interactor proteins
that were shown to influence the retention of rescued Phe508delCFTR at the PM. The group identified
a short list of candidate proteins that could constitute new targets for pharmacological modulation of
rescued Phe508del-CFTR stability at the PM of airway cells. Therefore, the objective of this project
was to validate and characterize the effect of 11 of these candidate proteins on the pharmacologically
rescued Phe508del-CFTR. We found that downregulation of Calgranulin, TCP-1-Theta and FLT-1 did
not change the abundance of rescued Phe508del-CFTR at the PM, but Tenascin-C downregulation did.
We suggest a role for Tenascin-C in regulating Phe508del-CFTR permanence at the PM. We observed
a reduction of rescued Phe508del-CFTR after Coronin 1C and Enigma knockdown, suggesting that
they affect CFTR ER-Golgi traffic. We saw a reduction on CFTR mRNA levels for Ku86 knockdown,
however this result still needs confirmation. We also demonstrated that βII Spectrin, PTRF, TG2 and
Lamin affected Phe508del-CFTR expression, and propose an additional role for βII Spectrin in
Phe508del-CFTR traffic to, and abundance at the PM.
Descrição
Tese de mestrado, Bioquímica e Biomedicina, 2023, Universidade de Lisboa, Faculdade de Ciências
Palavras-chave
Fibrose Quística CFTR Phe508del abundância de CFTR na membrana plasmática interactoma da CFTR Teses de mestrado - 2024