Project Portugal 2030

Summary

The driving hypothesis underlying PanEthnOrganoids is that cross-continental populations evolved independent natural protective mechanisms against infectious agents. Knowledge of these biological protections has huge potential translational applications in our arms race against infectious diseases, which are on the rise with climate changes, internationalization and destruction of natural environments. The project cross-fertilizes knowledge being produced in the Human Population Genetics field with the impressive advances in recent years in the Advanced 3D Modelling. In order to achieve the proposed goal, a proof-of-concept study of a bank of pan-ethnicity iPSC-derived organoids for advanced modelling of infectious diseases, the following set of specific objectives (SO) and corresponding activities will be considered: SO1. To implement advanced in vitro modelling of infectious diseases by establishing a core bank of ethnicity- and sex-balanced iPSC-derived organoids (Task 2) • Evaluate 30 iPSCs representing broad SSA, EUR and East Asian (EAS) ancestries (5 females and 5 males for each); • Generate stomach and liver organoids from the iPSCs; • Fully characterize the organoids organization and evaluate how far they represents the in vivo organ counterparts; • Maintain the bank of iPSC-derived organoids as a resource for future use. SO2. To model infection of stomach organoids by H. pylori and liver by DENV, towards a better understanding of host-pathogen interactions across ethnicities and sexes (Task 3 and 4) • Characterize the dynamics of H. pylori and DENV infections in the respective organoid models and compare it between ethnicities and sexes; • Perform multi-omics analyses: bulk and single-cell transcriptomics in H. pylori and DENV infected human organoids; • Elucidate the pathophysiological mechanisms and deregulated molecular pathways of H. pylori and DENV infections in the vital human organs across the three main ancestry backgrounds. SO3. To implement functional testing of hypotheses towards informing disease progression and therapeutic effectiveness across ethnicity and sex (Task 5) • Test candidate genes and drugs in the organoids to characterize the impact on H. pylori and DENV infections; • Evaluate the in vitro efficiency of candidate drugs and transferability between ethnicities; SO4. To disseminate PanEthnOrganoids results across publics, engage health stakeholders and explore innovation potential (Task 6) • Proactive dissemination of project outcomes, good practices and lessons learnt; • Engage key stakeholders and strategic target groups in the health field; • Explore innovation potential of the bank of pan-ethnicity iPSC-derived organoids.