myeloFateTune · Tuning Entry, Shaping Outcome: Receptor-scale control of brain myeloid fate and pathology in Alzheimer’s

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Project objective

Alzheimer’s disease upends the brain’s immune balance by admitting peripheral myeloid cells that intensify inflammation and damage. Two resident guardians from identical ontogeny, microglia in the parenchyma and border-associated macrophages at the brain’s interfaces, are non-redundant and normally sustain synapses and neurovascular health. Yet we still lack a human map of the receptor cues that decide whether incoming precursors settle as microglia or as border macrophages, and how that allocation shapes disease.This fellowship will close that gap. I will use a human microglia xenotransplantation model in which PSC-derived primitive myeloid precursors engraft into neonatal mouse brains, then apply a focused pooled CRISPR screen with high-parameter fate readouts to build the first receptor-to-fate atlas inside a living mammalian brain. Top receptor 'levers' will be rebuilt in arrayed lines and tested head to head by mosaic co-engraftment to obtain within-brain effect sizes. Fate will be coupled to function at Alzheimer-relevant endpoints such as plaque compaction, antigen presentation, lipid and oxidative tone, synaptic integrity, and vascular reactivity. Finally, I will translate these levers by programming primary human monocytes ex vivo to bias them toward microglia-like or border-like identities, followed by reinfusion, providing a realistic route for cell-based therapy. Together these steps convert descriptive atlases into manipulable circuitry and establish causal, human-specific checkpoints that steer myeloid allocation in vivo.By showing that allocation can be tuned and that tuning improves repair-linked programs, this project will deliver a therapeutic concept and a deployable toolkit: validated levers, minimal spectral panels, an identity scoring codebase, and FAIR data and protocols for the community. It will also accelerate my transition to independence at the interface of neuroimmunology, functional genetics, and high-dimensional cytometry.

Original text from CORDIS.

Participants

• VIB VZW · ZWIJNAARDE - GENTCoordinatorBelgium

Links

• View on CORDIS
• DOI: 10.3030/101286132