Descrizione del progetto
Mantenimento dell’idoneità cellulare negli ovociti dormienti
Le cellule germinali femminili, gli ovociti, possono sopravvivere per lunghi periodi mantenendo la capacità di creare un nuovo organismo. I meccanismi molecolari che consentono agli ovociti di eludere l’invecchiamento cellulare sono poco conosciuti. Il progetto ACTIVEDORMANCY, finanziato dal CER, intende scoprire i meccanismi alla base del mantenimento dell’idoneità cellulare e come questi meccanismi siano influenzati dall’invecchiamento, utilizzando tecnologie di imaging e omiche all’avanguardia. La dormienza degli ovociti coinvolge almeno due meccanismi unici recentemente scoperti: la soppressione del complesso mitocondriale I e l’attivazione costitutiva della risposta mitocondriale a proteine malpiegate. Il progetto in corso studierà gli adattamenti metabolici della sopravvivenza cellulare senza il complesso mitocondriale I, le proteine degli ovociti a lunga vita e la loro regolazione, nonché i meccanismi di controllo della qualità negli ovociti dormienti.
Obiettivo
Female germ cells, oocytes, have the remarkable ability to survive for long periods of time, up to 50 years in humans, while retaining the ability to give rise to a new organism. We know surprisingly little about the molecular mechanisms through which oocytes alleviate cellular ageing, and why such mechanisms eventually fail with advanced age.
The goal of this research proposal is to reveal both the mechanisms dormant oocytes employ to maintain cellular fitness and how ageing affects these mechanisms, combining biochemical perturbations with imaging and state-of-the-art -omics techniques. We have recently discovered that oocyte dormancy involves two mechanisms not reported in any animal cell type before: the suppression of mitochondrial complex I, and the constitutive activation of mitochondrial unfolded protein response. These discoveries point to a set of poorly understood strategies that oocytes use to minimise damage to their cellular components during their long lifespan. In this project, we focus on three new interlinked directions to reveal mechanisms that dormant oocytes employ to keep a ‘youthful’ cytoplasm: 1) Characterise the metabolic adaptations that enable life without mitochondrial complex I 2) Study extremely long-lived oocyte proteins and their regulation 3) Identify and characterise the quality control mechanisms that eventually fail in dormant oocytes to impact fertility. We will use oocytes from frogs, mice, and humans which are complementary in their ease of handling and relevance to human physiology.
One of the biggest problems developed nations face is late-motherhood and associated fertility problems due to ageing oocytes. >25% of female fertility problems are unexplained, pointing to a huge gap in our understanding of female reproduction. This proposal will help fill this gap by studying longevity mechanisms in dormant oocytes. It will further provide insights into the metabolic adaptations of long-lived cells, female fertility, and ageing.
Campo scientifico
Parole chiave
Programma(i)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Argomento(i)
Meccanismo di finanziamento
HORIZON-ERC - HORIZON ERC GrantsIstituzione ospitante
08003 Barcelona
Spagna