Interrogating human disease by transcriptomic and proteomic profiling in a sheep model for atrial fibrillation

• Autores: Alba Alvarez Franco
• Directores de la Tesis: Miguel Manzanares Fourcade (dir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2021
• Idioma: inglés
• Número de páginas: 171
• Títulos paralelos:
  • Interrogando la enfermedad humana mediante transcriptomica y proteomica en un modelo de oveja de Fibrilación Auricular
• Tribunal Calificador de la Tesis: Joaquín Dopazo Blázquez (presid.), María Gómez Vicentefranqueira (secret.), Fátima Sánchez Cabo (voc.), Ana María Rojas Mendoza (voc.), Ozren Bogdanovic Kupesic (voc.)
• Programa de doctorado: Programa de Doctorado en Biociencias Moleculares por la Universidad Autónoma de Madrid
• Materias:
  • Ciencias médicas
• Enlaces
  • Tesis en acceso abierto en: Biblos-e Archivo
• Resumen

  • Atrial fibrillation (AF) is a progressive cardiac arrhythmia that increases the risk of hospitalization and adverse cardiovascular events. AF is a complex disease with multiple risk factors and associated comorbidities [74, 126] and remarkably, among them, AF is associated with a 5-fold risk of stroke [100]. The global incidence is expected to double the current rates by 2050, and as the global population increases its longevity, understanding the consequences of AF on an aged population becomes more critical. Although AF has been under extensive research for more than 50 years, there is a clear demand for more inclusive and large-scale approaches to understand the molecular drivers responsible for AF, as well as the fundamental mechanisms governing the transition from paroxysmal to persistent and permanent forms. In this doctoral thesis project, we have taken advantage of a well-established model of tachypacing-induced long-standing AF in the sheep to analyse in vivo the molecular changes that occur in the atria and systemically during the progression of AF from paroxysmal to its long-lasting forms, always in comparison with paired surgically operated sinus rhythm controls. We have performed transcriptomic and proteomic profiling of atrial tissue and cardiomyocytes aswell as profiling the blood proteome. For the analysis of data, we have developed our own pipelines, benchmarked different tools and carried out correlation-based integration analysis and hierarchical modelling of longitudinal data in a Bayesian framework. We demonstrate that the hallmarks of AF-induced atrial remodelling change only at early transitional stages at the molecular level, but remain unaltered at later stages of the disease and that the left atrium undergoes significantly more profound changes in its expression programme than the right atrium. By dissecting the short time window between the paroxysmal and persistent forms, we proved that electrical remodelling occurring in the left atria is sufficient to trigger molecular changes in less than a few hours and we have confirmed that the pro-thrombotic state, inflammation, and lipid metabolism are activated systemically as the result of AF per se, beyond being these processes associated with pre-existing comorbidities. This pattern of dynamic changes in gene and protein expression replicate the electrical and structural remodelling previously shown in animal models and in humans, and uncover novel mechanisms potentially relevant for disease treatment