Study of molecular causes underlying Williams-Beuren syndrome phenotype through the development of novel therapeutic approaches

Ortiz Romero, Paula

Study of molecular causes underlying Williams-Beuren syndrome phenotype through the development of novel therapeutic approaches

Document Type

Doctoral thesis
Published Version

Author

Ortiz Romero, Paula

Director

Campuzano Uceda, María Victoria

Publication Date

2019-11-18

Pages

219 p.

Citation

Ortiz Romero, P. Study of molecular causes underlying Williams-Beuren syndrome phenotype through the development of novel therapeutic approaches. Universitat Pompeu Fabra; 2019. handle: http://hdl.handle.net/10803/667953

This citation was generated automatically.

Doctoral program

Programa de doctorat en Biomedicina

Abstract

Williams-Beuren syndrome (WBS) is a rare neurodevelopmental disorder caused by a heterozygous deletion of ~1.5 Mb in chromosome region 7q11.23. The use of murine models of the disease has helped to broaden the knowledge about the syndrome and the role of the affected genes and pathways, but a deep insight of the molecular basis of the disease would be of great interest for the development of possible treatments. We have used a WBS mouse model carrying a heterozygous deletion that mimics the most common deletion found in patients. We have characterized the vascular phenotype of these animals and identified molecular alterations relevant for both the neurocognitive and cardiovascular phenotypes of the disease. In addition, we have performed preclinical tests of two novel therapeutic approaches. The results highlight the importance of this model for the study of molecular mechanisms underlying the disease and the evaluation of the effect of new therapeutic strategies.
La síndrome de Williams-Beuren (WBS) és una malaltia rara del neurodesenvolupament causada per una deleció heterozigota de ~1.5 Mb a la regió cromosòmica 7q11.23. L’ús de models murins de la malaltia ha contribuït a ampliar el coneixement sobre la síndrome i la funció dels gens i vies afectats, però conèixer les bases moleculars de la malaltia seria de gran interès per al desenvolupament de possibles tractaments. Hem utilitzat un model de ratolí de la WBS portador d’una deleció heterozigota que mimetitza la deleció més comú trobada en pacients. Hem caracteritzat el fenotip vascular d’aquests animals i identificat alteracions moleculars rellevants tant per al fenotip neurocognitiu com cardiovascular associats a la malaltia. A més, hem dut a terme assajos preclínics amb dues aproximacions terapèutiques innovadores. Els resultats remarquen la importància d’aquest model per a l’estudi dels mecanismes moleculars subjacents a la malaltia i per a l’avaluació de l’efecte de noves estratègies terapèutiques.

Keywords

Williamas-Beuren syndrome (WBS), Murine models, Oxidative stress, Calcium homeostasis, Therateupic approaches, Síndrome de Williams-Beuren (SWB), Models murins, Estrès oxidatiu, Homeòstasi de calci, Aproximacions terapèutiques