Description du projet
Maintien de l’aptitude cellulaire dans les ovocytes dormants
Les cellules germinales femelles, les ovocytes, peuvent survivre de longues périodes tout en conservant leur capacité de créer un nouvel organisme. Les mécanismes moléculaires qui permettent aux ovocytes d’échapper au vieillissement cellulaire sont encore mal compris. Le projet ACTIVEDORMANCY, financé par le CER, entend découvrir les mécanismes qui sous-tendent le maintien de la santé cellulaire et la manière dont ces mécanismes sont affectés par le vieillissement, en faisant appel à l’imagerie et à des technologies omiques de pointe. La dormance des ovocytes implique au moins deux mécanismes uniques récemment découverts: la suppression du complexe I mitochondrial et l’activation constitutive de la réponse des protéines mitochondriales non pliées. Le projet étudiera les adaptations métaboliques de la survie cellulaire sans complexe I mitochondrial, les protéines ovocytaires à longue durée de vie et leur régulation, ainsi que les mécanismes de contrôle de la qualité des ovocytes dormants.
Objectif
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.
Champ scientifique
Mots‑clés
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Régime de financement
HORIZON-ERC - HORIZON ERC GrantsInstitution d’accueil
08003 Barcelona
Espagne