New therapeutic approaches to target myofibroblast activation in liver pathologies: fibrosis and cholangiocarcinoma

[eng] HYPOTHESES: Iron accumulation and senescence mediate fibrosis progression in kidney and lung. In the liver, iron overload, specifically in hepatocytes, has been linked to hepatic diseases such as hereditary hemochromatosis, MASLD or ALD. Therefore, we hypothesized that iron and senescence coul...

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Detalles Bibliográficos
Autor: Amengual Segura, Josep
Tipo de recurso: tesis doctoral
Estado:Versión publicada
Fecha de publicación:2024
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/219675
Acceso en línea:https://hdl.handle.net/2445/219675
http://hdl.handle.net/10803/693991
Access Level:acceso abierto
Palabra clave:Malalties del fetge
Envelliment
Tumors
Ferro en l'organisme
Liver diseases
Aging
Iron in the body
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spelling New therapeutic approaches to target myofibroblast activation in liver pathologies: fibrosis and cholangiocarcinomaAmengual Segura, JosepMalalties del fetgeEnvellimentTumorsFerro en l'organismeLiver diseasesAgingIron in the body[eng] HYPOTHESES: Iron accumulation and senescence mediate fibrosis progression in kidney and lung. In the liver, iron overload, specifically in hepatocytes, has been linked to hepatic diseases such as hereditary hemochromatosis, MASLD or ALD. Therefore, we hypothesized that iron and senescence could have a role in liver fibrosis progression, and in this context, an iron chelator could become a potential therapeutic approach. Preliminary results from our group showed that in CCA, TGF-β has tumour suppressor effects. However, TGF-β has been linked to protumorigenic effects in the TME. Previous literature indicated that NOX4 plays a role downstream TGF-β in hepatic stellate cell activation towards matrix-producing myofibroblasts. This evidence suggested that NOX4 could be playing a role in CAF activation in CCA. Since CAF support and promote CCA progression and chemoresistance, we hypothesized that targeting NOX4 could have therapeutic effects. OBJECTIVES: Analysis of iron chelation as a new therapeutic approach in liver fibrosis. To evaluate whether iron accumulates, correlating with characteristics of cell senescence, in a mouse model of liver fibrosis induced by CCl4. Evaluation of iron chelation by deferiprone as a therapeutic approach for liver fibrosis in vivo. Analysis of the efficacy of deferiprone to attenuate iron accumulation and senescence in vitro. To explore the translational relevance of iron accumulation and senescence in the development of liver fibrosis in patients. Analysis of the potential therapeutic role of targeting NOX4 in hepatic stellate cell activation. Implications in cholangiocarcinoma. Analysis of NOX4 expression in CCA tumour and stromal cells. Generation and characterization of a syngeneic orthotopic CCA model in wild type and NOX4-/- mice to evaluate the role of stromal NOX4 on tumour progression. Generation of loss of function experimental models of NOX4 in human hepatic stellate cells by CRISPR-Cas9 and siRNA to analyse transdifferentiation into myofibroblasts in vitro. Evaluation of the efficacy of NOX4 inhibitors on HSC transdifferentiation in vitro. Evaluation of the efficacy of NOX4 inhibitors on tumour progression in a murine AKT-YAP hydrodynamic tail vein injection CCA model.Universitat de BarcelonaFabregat Romero, IsabelVaquero Rodríguez, JavierUniversitat de Barcelona. Facultat de Medicina i Ciències de la Salut2024info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/219675http://hdl.handle.net/10803/693991Tesis Doctorals - Facultat - Medicina i Ciències de la Salutreponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglés(c) Amengual Segura, Josep, 2025info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/2196752026-05-27T06:46:51Z
dc.title.none.fl_str_mv New therapeutic approaches to target myofibroblast activation in liver pathologies: fibrosis and cholangiocarcinoma
title New therapeutic approaches to target myofibroblast activation in liver pathologies: fibrosis and cholangiocarcinoma
spellingShingle New therapeutic approaches to target myofibroblast activation in liver pathologies: fibrosis and cholangiocarcinoma
Amengual Segura, Josep
Malalties del fetge
Envelliment
Tumors
Ferro en l'organisme
Liver diseases
Aging
Iron in the body
title_short New therapeutic approaches to target myofibroblast activation in liver pathologies: fibrosis and cholangiocarcinoma
title_full New therapeutic approaches to target myofibroblast activation in liver pathologies: fibrosis and cholangiocarcinoma
title_fullStr New therapeutic approaches to target myofibroblast activation in liver pathologies: fibrosis and cholangiocarcinoma
title_full_unstemmed New therapeutic approaches to target myofibroblast activation in liver pathologies: fibrosis and cholangiocarcinoma
title_sort New therapeutic approaches to target myofibroblast activation in liver pathologies: fibrosis and cholangiocarcinoma
dc.creator.none.fl_str_mv Amengual Segura, Josep
author Amengual Segura, Josep
author_facet Amengual Segura, Josep
author_role author
dc.contributor.none.fl_str_mv Fabregat Romero, Isabel
Vaquero Rodríguez, Javier
Universitat de Barcelona. Facultat de Medicina i Ciències de la Salut
dc.subject.none.fl_str_mv Malalties del fetge
Envelliment
Tumors
Ferro en l'organisme
Liver diseases
Aging
Iron in the body
topic Malalties del fetge
Envelliment
Tumors
Ferro en l'organisme
Liver diseases
Aging
Iron in the body
description [eng] HYPOTHESES: Iron accumulation and senescence mediate fibrosis progression in kidney and lung. In the liver, iron overload, specifically in hepatocytes, has been linked to hepatic diseases such as hereditary hemochromatosis, MASLD or ALD. Therefore, we hypothesized that iron and senescence could have a role in liver fibrosis progression, and in this context, an iron chelator could become a potential therapeutic approach. Preliminary results from our group showed that in CCA, TGF-β has tumour suppressor effects. However, TGF-β has been linked to protumorigenic effects in the TME. Previous literature indicated that NOX4 plays a role downstream TGF-β in hepatic stellate cell activation towards matrix-producing myofibroblasts. This evidence suggested that NOX4 could be playing a role in CAF activation in CCA. Since CAF support and promote CCA progression and chemoresistance, we hypothesized that targeting NOX4 could have therapeutic effects. OBJECTIVES: Analysis of iron chelation as a new therapeutic approach in liver fibrosis. To evaluate whether iron accumulates, correlating with characteristics of cell senescence, in a mouse model of liver fibrosis induced by CCl4. Evaluation of iron chelation by deferiprone as a therapeutic approach for liver fibrosis in vivo. Analysis of the efficacy of deferiprone to attenuate iron accumulation and senescence in vitro. To explore the translational relevance of iron accumulation and senescence in the development of liver fibrosis in patients. Analysis of the potential therapeutic role of targeting NOX4 in hepatic stellate cell activation. Implications in cholangiocarcinoma. Analysis of NOX4 expression in CCA tumour and stromal cells. Generation and characterization of a syngeneic orthotopic CCA model in wild type and NOX4-/- mice to evaluate the role of stromal NOX4 on tumour progression. Generation of loss of function experimental models of NOX4 in human hepatic stellate cells by CRISPR-Cas9 and siRNA to analyse transdifferentiation into myofibroblasts in vitro. Evaluation of the efficacy of NOX4 inhibitors on HSC transdifferentiation in vitro. Evaluation of the efficacy of NOX4 inhibitors on tumour progression in a murine AKT-YAP hydrodynamic tail vein injection CCA model.
publishDate 2024
dc.date.none.fl_str_mv 2024
dc.type.none.fl_str_mv info:eu-repo/semantics/doctoralThesis
info:eu-repo/semantics/publishedVersion
format doctoralThesis
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/219675
http://hdl.handle.net/10803/693991
url https://hdl.handle.net/2445/219675
http://hdl.handle.net/10803/693991
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv (c) Amengual Segura, Josep, 2025
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Amengual Segura, Josep, 2025
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Universitat de Barcelona
publisher.none.fl_str_mv Universitat de Barcelona
dc.source.none.fl_str_mv Tesis Doctorals - Facultat - Medicina i Ciències de la Salut
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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