Descrizione del progetto
Imparare come prevenire la cardiopatia ischemica dall’eterocefalo glabro
La coronaropatia è una delle principali cause di decesso al mondo e la sua patogenesi è stata collegata ad anomalie metaboliche. L’eterocefalo glabro è un singolare modello di roditore con una vita straordinariamente lunga e sana (> 36 anni); tale animale presenta un metabolismo cardiaco atipico che gli permette di adattarsi a condizioni ambientali di estrema ipossia e fa sì che la sua funzione cardiaca declini solo in modo trascurabile con l’avanzare dell’età. Precedenti lavori svolti dal team del progetto METAMOLE, finanziato dall’UE, hanno rivelato che gli eterocefali glabri possono sopravvivere per lunghi periodi di tempo in condizioni di ipossia estrema, modificando il proprio metabolismo in modo da utilizzare il fruttosio. L’obiettivo del progetto METAMOLE è impiegare le tecnologie omiche per studiare le modifiche genetiche, epigenetiche e post-traslazionali alla base delle caratteristiche metaboliche, della tolleranza all’ipossia e delle ottime condizioni miocardiche dell’eterocefalo glabro.
Obiettivo
The overarching aim of this proposal is to identify unique features of naked mole-rat cardiac metabolism that serve as advantageous adaptations to deal with a hypoxic environment, a state relevant to heart disease. Coronary heart disease is a leading cause of death and its pathogenesis has been linked to metabolic abnormalities. The naked mole–rat has recently emerged as a rodent model of interest to biomedicine due to its extraordinarily long and healthy lifespan (>36 years). Naked mole-rats exhibit various atypical cardiac features including a remodelled metabolism that serve as adaptations to their extremely hypoxic and hypercapnic environment, and also contribute to the negligible decline in heart function with age. I will use “omics” technologies to examine the genetic, epigenetic and post-translational features underlying naked mole-rat rewired metabolism, hypoxia tolerance and myocardial fitness. I have shown that the naked mole-rat can survive extended periods under extreme hypoxia without apparent damage, by switching its metabolism to utilise fructose. Use of fructose in ischaemic conditions could therefore prove beneficial in other mammals. I will assess whether enhancing fructose metabolism via transgenic mouse models is protective under ischaemic conditions. I have shown that the transcriptional landscape of the naked mole-rat myocardium has preserved several neonatal-like features. Since neonatal mammalian heart has regenerative capacity, a quality that is quickly lost after birth, naked mole-rats may be the first adult mammalian model for heart regeneration. This project will measure regenerative capacity of the adult naked mole-rat heart and the mechanisms by which it may retain its proliferative competency. By introducing these features into the mouse I aim to validate and understand the benefit of these unique traits in promoting a healthy myocardium with possibilities for translating these discoveries into novel therapeutic strategies in man.
Campo scientifico
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-STG - Starting GrantIstituzione ospitante
50937 Koeln
Germania