A mathematical model of the phosphoinositide pathway in human pulmonary epithelial cells

Bibliographic Details
Main Author: Olivença, Daniel Vigário, 1976-
Publication Date: 2018
Language: eng
Source: Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
Download full: http://hdl.handle.net/10451/35920
Summary: Tese de doutoramento, Biologia (Biologia de Sistemas), Universidade de Lisboa, Faculdade de Ciências, 2018
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spelling A mathematical model of the phosphoinositide pathway in human pulmonary epithelial cellsTeses de doutoramento - 2018Domínio/Área Científica::Ciências Naturais::Ciências BiológicasTese de doutoramento, Biologia (Biologia de Sistemas), Universidade de Lisboa, Faculdade de Ciências, 2018Cystic fibrosis is a condition caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride and bicarbonate channel. The epithelial sodium channel (ENaC) may also be affected. The defective function of these ion channels is thought to reduce the airway surface liquid (ASL) and lead to the accumulation of mucus in the airways that characterizes the disease and causes the recurrent pulmonary infections and inflammation that will ultimately destroy the lungs of the affected subjects. Phosphoinositides are rare signaling lipids that constitute a complex network regulating many cellular processes. One of phosphoinositides’ many functions is as cell membrane protein regulators, and several studies implicate phosphatidylinositol 4,5-biphosphate (PI(4,5)P2) in ENaC regulation. Diacylglycerol kinase (DGK), an enzyme of the phosphoinositide pathway that catalyses the phosphorylation of diacylglycerol (DAG) into phosphatidic acid (PA). When DGK is inhibited, it will cause the moderation of ENaC function, and this could be exploited as a therapeutic in cystic fibrosis. But the mechanism of ENaC regulation by DGK is not completely understood. The usually accepted hypothesis is that DGK influences PI(4,5)P2 production by halting the phosphoinositide recycling. In Chapter 2 we present a model of the phosphoinositide pathway that simulates one square micrometer of the inner layer of the membrane. The objective of this project was to create a model that could simulate the phosphoinositide pathway and be used to study how perturbations to the pathway impact the levels of pertinent lipids, especially the ones known to affect ENaC. The model replicates the steady-state of the phosphoinositide pathway as recorded in the literature and replicates most known dynamic phenomena. Furthermore, sensitivity analysis demonstrates that the model is robust to moderate perturbations to the parameters. The model suggests that the main source of material to the PI(4,5)P2 pool is a flux representing the direct transformation of phosphatidylinositol (PI) into PI(4,5)P2 that defies the traditional view that the main source is the sequential phosphorylation of phosphoinositol into phosphatidylinositol 4-phosphate (PI(4)P) by the enzyme phosphoinositol 4-kinase (PI4K) followed by the transformation to PI(4,5)P2 by phosphoinositide 4-phosphate 5-kinase I (PIP5KI). The model also suggests that phosphatidylinositol 5-phosphate (PI(5)P) could be a significant source for PI(4,5)P2 production. We compared the model results to data from a siRNA screens, where the expression of several enzymes in the pathway were knocked down and the activity of ENaC was monitored. Our model suggests control strategies where the activity of the enzyme PIP5KI or the PI4 +PIP5K +DVL protein complex are decreased and cause an efficacious reduction in PI(4,5)P2 levels while avoiding undesirable alterations in other phosphoinositide pools. In Chapter 3 we present a model that enables the study of the interplay between ENaC, CFTR, airway surface liquid (ASL), PI(4,5)P2 and the protein SPLUNC1 (short palate, lung, and nasal epithelial clone). It presents a good fit to experimental observations, and the available data can constrain the model’s parameters without ambiguities. The model analysis shows that ASL at the steady state is sensitive to small changes in PI(4,5)P2 abundance, particularly in cystic fibrosis conditions, which suggests that manipulation of phosphoinositide metabolism may promote therapeutic benefits for cystic fibrosis patients. Finally, in Chapter 4, we bring the phophoinositide pathway and ENaC/ASL model together. These models enabled us to study DGK and ENaC and strongly suggest that, contrary to the usually accepted hypothesis, this regulation is effected by the control of PI(4,5)P2 production by the PIP5KI that in turn is controlled by PA, the product of DGK. In this work we also use a model of the phosphoinositide cycle to test the hypothesis that DGK influence PI(4,5)P2 production by halting the phosphoinositide recycling. This model is unable to replicate the available data if the activation of PIP5KI by PA is not implemented, which strengthens our belief that ENaC regulation by phosphoinositides is accomplished through PA and PIP5KI.Fundação para a Ciência e a Tecnologia (FCT), SFRH/BD/52486/2014; Programa doutoral - BioSys em Sistemas Biológicos, Genómica Funcional & Integrativa, (FCT/PD/00065/2012)Pinto, Francisco R.Voit, EberhardRepositório da Universidade de LisboaOlivença, Daniel Vigário, 1976-2018-12-17T11:57:19Z201820182018-01-01T00:00:00Zdoctoral thesisinfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10451/35920TID:101508832enginfo:eu-repo/semantics/openAccessreponame:Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)instname:FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiainstacron:RCAAP2025-03-17T13:59:14Zoai:repositorio.ulisboa.pt:10451/35920Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireinfo@rcaap.ptopendoar:https://opendoar.ac.uk/repository/71602025-05-29T02:59:59.231014Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) - FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiafalse
dc.title.none.fl_str_mv A mathematical model of the phosphoinositide pathway in human pulmonary epithelial cells
title A mathematical model of the phosphoinositide pathway in human pulmonary epithelial cells
spellingShingle A mathematical model of the phosphoinositide pathway in human pulmonary epithelial cells
Olivença, Daniel Vigário, 1976-
Teses de doutoramento - 2018
Domínio/Área Científica::Ciências Naturais::Ciências Biológicas
title_short A mathematical model of the phosphoinositide pathway in human pulmonary epithelial cells
title_full A mathematical model of the phosphoinositide pathway in human pulmonary epithelial cells
title_fullStr A mathematical model of the phosphoinositide pathway in human pulmonary epithelial cells
title_full_unstemmed A mathematical model of the phosphoinositide pathway in human pulmonary epithelial cells
title_sort A mathematical model of the phosphoinositide pathway in human pulmonary epithelial cells
author Olivença, Daniel Vigário, 1976-
author_facet Olivença, Daniel Vigário, 1976-
author_role author
dc.contributor.none.fl_str_mv Pinto, Francisco R.
Voit, Eberhard
Repositório da Universidade de Lisboa
dc.contributor.author.fl_str_mv Olivença, Daniel Vigário, 1976-
dc.subject.por.fl_str_mv Teses de doutoramento - 2018
Domínio/Área Científica::Ciências Naturais::Ciências Biológicas
topic Teses de doutoramento - 2018
Domínio/Área Científica::Ciências Naturais::Ciências Biológicas
description Tese de doutoramento, Biologia (Biologia de Sistemas), Universidade de Lisboa, Faculdade de Ciências, 2018
publishDate 2018
dc.date.none.fl_str_mv 2018-12-17T11:57:19Z
2018
2018
2018-01-01T00:00:00Z
dc.type.driver.fl_str_mv doctoral thesis
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10451/35920
TID:101508832
url http://hdl.handle.net/10451/35920
identifier_str_mv TID:101508832
dc.language.iso.fl_str_mv eng
language eng
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
instname:FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia
instacron:RCAAP
instname_str FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia
instacron_str RCAAP
institution RCAAP
reponame_str Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
collection Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
repository.name.fl_str_mv Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) - FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia
repository.mail.fl_str_mv info@rcaap.pt
_version_ 1833601557315190784

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