Dissecting Microglia vulnerability to STress response in Multiple Sclerosis through human iPSC modelling
| Title | Dissecting Microglia vulnerability to STress response in Multiple Sclerosis through human iPSC modelling |
|---|---|
| Acronym | MiST-MS |
| Start date | 2026-01-01 |
| End date | 2030-12-31 |
| Sponsor | European Research Council - Starting Grant (ERC-StG) |
| Institution | Humanitas University |
Associated cell lines
Project Description
Shifting from the traditional focus on central nervous system-targeting lymphocytes, MiST-MS posits that glial responses, particularly cellular senescence, are required to compartmentalized self-sustaining chronic inflammation in multiple sclerosis (MS) and related long-term clinical outcomes, including disability. MiST-MS is specifically designed to address the urgent need to identify new therapeutic targets to halt MS clinical progression through two interconnected research lines. The project will first identify cell-specific perturbations and molecular pathways associated with inflammation-driven early brain aging using MS human iPSC-derived microglia and genome-wide CRISPR-Cas9 screenings. By employing cutting-edge computational methodologies (single-cell CRISPR-seq, multi-omics integration, composite assessment, and cellular networking/signaling), MiST-MS offers a unique opportunity to identify and dissect mechanisms underlying microglia resilience versus vulnerability and their impact on stress responses, both independently and within the context of hiPSC-derived inflamed glia-enriched brain organoids. MiST-MS represents a ground-breaking modeling pipeline to study inflammation-driven early brain aging in MS. At the patient-level, since MS patients with evidence of smoldering inflammation (marked by the presence of chronic active lesions by in vivo MRI) exhibit poor tissue repair capacity and worse clinical outcomes, the project will also aim to identify common and divergent glial and neuronal responses between MS patients with and without chronic active lesions generating human iPSC lines for personalized medicine applications. In summary, MiST-MS is a highly innovative interdisciplinary project that provides an unprecedented understanding of microglia states in response to injury and streamlines the rational design of future therapies to mitigate chronic inflammation-driven premature brain aging and halt MS clinical progression.