Logo do repositório
 
Publicação

Role of CFTR in Epithelial Differentiation by Functional Genomics

2020-11Tese de doutoramento Acesso aberto
Ver registo simples
datacite.subject.fosCiências Naturais::Ciências Biológicaspt_PT
dc.contributor.advisorAmaral, Margarida
dc.contributor.advisorChanson, Marc
dc.contributor.authorSousa, Luís Miguel dos Santos
dc.date.accessioned2021-06-14T11:11:47Z
dc.date.available2021-06-14T11:11:47Z
dc.date.issued2020-11
dc.date.submitted2020-07
dc.description.abstractCystic Fibrosis (CF) is caused by mutations in the CFTR gene. The relationship between CFTR and differentiation has been firmly documented. However, the mechanisms that regulate this relationship are still unclear. The aim of this work was to further characterize the differentiation defect in CF and to identify the underlying molecular mechanisms. In the first chapter, our results show that CF cells display increased proliferation, acquire lower levels of TEER upon polarization, display slower wound healing, and have altered differentiation. Moreover, our data suggest that partial epithelial-mesenchymal transition occurs in CF cells. Given that Krüppel-like factors (KLFs) play pivotal roles in the regulation of differentiation, in the second chapter we tested the levels of KLF2, 4 and 5 and found that only KLF4 is differentially expressed in CF vs non-CF cells. Therefore, we then assessed whether KLF4 modulation had an impact in CFTR levels and function. Our data show that KLF4 acts as a negative regulator of wt-CFTR expression and function. Noteworthy, F508del cells are relatively insensitive to KLF4 modulation. Next, we tested possible pathways by which KLF4 action can impact CFTR in the CF and non-CF contexts. Our data showed that AKT signalling acts as a modulator of CFTR in a KLF4-dependent way, whilst GSK3β was observed to be a negative regulator of CFTR independent of KLF4 in CF cells. In chapter three, our data show that KLF4 knock-out has no major impact in proliferation but modulates TEER acquisition, wound healing, and differentiation markers differentially in CF vs non-CF cells. Moreover, we characterized the levels of KLFs, CFTR and proteins of interest during epithelial differentiation and showed that maximum KLF4 expression occurs prior to maximum CFTR expression. Altogether these data contribute to mechanistic clarification of the relationship between CFTR and epithelial differentiation.pt_PT
dc.identifier.tid101546440pt_PT
dc.identifier.urihttp://hdl.handle.net/10451/48522
dc.language.isoengpt_PT
dc.relationFCT /PD/00065/2012pt_PT
dc.relationRole of CFTR in epithelial differentiation by functional genomics
dc.subjectFibrose Quísticapt_PT
dc.subjectKLF4pt_PT
dc.subjectDiferenciação epitelialpt_PT
dc.subjectAKTpt_PT
dc.subjectEMTpt_PT
dc.subjectCystic Fibrosispt_PT
dc.subjectEpithelial differentiationpt_PT
dc.subjectAKT signallingpt_PT
dc.titleRole of CFTR in Epithelial Differentiation by Functional Genomicspt_PT
dc.typedoctoral thesis
dspace.entity.typePublication
oaire.awardNumberPD/BD/106087/2015
oaire.awardTitleRole of CFTR in epithelial differentiation by functional genomics
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//PD%2FBD%2F106087%2F2015/PT
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typedoctoralThesispt_PT
relation.isProjectOfPublication83823489-3c65-4dee-9a6f-03149d37fb91
relation.isProjectOfPublication.latestForDiscovery83823489-3c65-4dee-9a6f-03149d37fb91
thesis.degree.nameTese de doutoramento, Biologia (Biologia de Sistemas), Universidade de Lisboa, Faculdade de Ciências, 2020pt_PT

Ficheiros

Principais
A mostrar 1 - 1 de 1
Miniatura
Nome:
ulsd735655_td_Luis_Sousa.pdf
Tamanho:
7.82 MB
Formato:
Adobe Portable Document Format
Ver/Abrir

Coleções

FC - Teses de Doutoramento