[HIBRID] Deciphering the genetic and molecular determinants of trophoblast development during human embryo implantation
Ente: EC
Scadenza: 2029-08-31
Importo max: 214.345 EUR
Paese: EU
Descrizione
After fertilisation, the human embryo undergoes several divisions forming a free-floating blastocyst, which implants into the endometrium a week later. Implantation failure is responsible for 40-70% of pregnancy losses and is caused by the inability of the blastocyst to form a trophoblast envelope that embeds in the endometrium, but little is known about the regulators of trophoblast development during this critical time. Moreover, the deep embedding of the human blastocyst, termed interstitial implantation, is a unique human feature and considered to be the newest evolutionary innovation, distinct from the ancestral superficial mechanisms.
We hypothesise that the formation of the deeply embedded trophoblast envelope is regulated by the activity of specific transcription factors (TFs) that govern cellular ability to proliferate and migrate. Given that interstitial implantation has evolved mainly in Great apes, we hypothesise that evolutionary changes in the genetic sequences of Cis-Regulatory Elements (CREs) controlling the activity of these TFs have contributed to deep embedding. To test our hypotheses, we will model implantation by placing human blastoids on hydrogels containing endometrial cells and generate multiomics data from implanting trophoblasts to model their gene regulatory networks (GRNs). We will functionally validate TFs central to these GRNs using genetically engineered blastoids. Next, we will use a neural convolutional network model to select CREs whose change in accessibility correlate with the depth of embedding in dierent species. Finally, we will validate the functions of these CREs using genetically engineered blastoids in our implantation model.
This project aims to identify key regulators of trophoblast development during implantation and to clarify how genetic sequences impact implantation outcomes, providing insight into the fragility of human pregnancy.
Settori: Horizon Europe Topics
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