Mechanistic lnsights into Hereditary Tyrosinemia Type I and the Rational Screening of Pharmacological Chaperones
- Autores: Jon Gil Martínez
- Directores de la Tesis: Óscar Millet Aguilar-Galindo (dir. tes.), Alicia Alonso Izquierdo (tut. tes.)
- Lectura: En la Universidad del País Vasco - Euskal Herriko Unibertsitatea ( España ) en 2026
- Idioma: inglés
- Programa de doctorado: Programa de Doctorado en Biología Molecular y Biomedicina / Molecular Biology and Biomedicine por la Universidad del País Vasco/Euskal Herriko Unibertsitatea
- Calificación: Sobresaliente Cum Laude
- Materias:
- Enlaces
- Tesis en acceso abierto en: ADDI
- Resumen
Hereditary Tyrosinemia Type 1 (HTl) is an autosomal recessive rare disease caused by Fumarylacetoacetate Hydrolase (FAH) deficiency. Treatment with nitisinone (NTBC) significantly improves the life expectancy of HTl patients by avoiding the buildup of toxic metabolites, still presenting sorne adverse effects. This thesis presents a metabolic characterization of a novel mouse model bearing the p.G337S mutation in its Fah gene, revealing sorne new important aspects of HTl pathophysiology such as the downregulation of tyrosine catabolism as an oxidative stress response mediated by Nrf2 transcription factor or the impairment of gluconeogenesis due to low epinephrine levels. Both phenomena occur as a direct consequence of HTl -related toxic metabolite accumulation and can be corrected by NTBC therapy. However, since a therapy enabling deficient FAH to accomplish its function would be preferable, a structure-based drug screening to develop pharmacological chaperones that stabilize human recombinant FAH is also presented in this thesis, paving the way for future therapeutic alternatives to treat HTl.
