Modulating the hippo pathway as novel strategy for beta-cell-directed therapy in diabetes
Datei | Beschreibung | Größe | Format | |
---|---|---|---|---|
Dissertation_Lupse.pdf | 29.13 MB | Adobe PDF | Anzeigen |
Autor/Autorin: | Lupše, Blaž | BetreuerIn: | Mädler, Kathrin | 1. GutachterIn: | Mädler, Kathrin | Weitere Gutachter:innen: | Battelino, Tadej Gauthier, Benoit |
Zusammenfassung: | Pancreatic β-cell failure is the key pathogenic element of the complex metabolic deterioration in type 2 diabetes (T2D). The Pleckstrin homology domain leucine-rich repeat protein phosphatases (PHLPPs) are novel therapeutic targets for the restoration of β-cell survival and function in diabetes. PHLPP levels are highly elevated in metabolically stressed human and rodent diabetic β-cells. Sustained hyper-activation of mechanistic target of rapamycin complex 1 (mTORC1) is the primary mechanism of the PHLPP upregulation linking chronic metabolic stress to ultimate β-cell death. PHLPPs directly dephosphorylate and regulate activities of β-cell survival-dependent kinases AKT and MST1, constituting a regulatory triangle loop to control β-cell apoptosis. Inhibition of PHLPPs markedly improves β-cell survival and function in experimental models of diabetes in vitro, in vivo, and in primary human T2D islets. Our research defines an important mechanism of β-cell failure in diabetes and demonstrates the functional significance of targeting PHLPPs in restoring pancreatic β-cell mass in diabetes. |
Schlagwort: | Pancreatic islets; beta-cells; apoptosis | Veröffentlichungsdatum: | 15-Jun-2022 | Dokumenttyp: | Dissertation | DOI: | 10.26092/elib/1779 | URN: | urn:nbn:de:gbv:46-elib62176 | Institution: | Universität Bremen | Fachbereich: | Fachbereich 02: Biologie/Chemie (FB 02) |
Enthalten in den Sammlungen: | Dissertationen |
Seitenansichten
191
checked on 26.11.2024
Download(s)
217
checked on 26.11.2024
Google ScholarTM
Prüfe
Diese Ressource wurde unter folgender Copyright-Bestimmung veröffentlicht: Lizenz von Creative Commons