Project Details
Projekt
Microglia instruct the toxic microenvironment in transplantable leukodystrophies
Subject Area
Molecular and Cellular Neurology and Neuropathology
Clinical Neurology; Neurosurgery and Neuroradiology
Clinical Neurology; Neurosurgery and Neuroradiology
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 500301720
The Aim of this project is to define the neurotoxic disease mechanisms in CSF1R-related leukoencephalopathy (CSF1R-LE), a genetic microgliopathy, cerebral X-linked adrenoleukodystrophy (CALD), a metabolic microgliopathy, and multiple sclerosis (MS), an inflammatory disease with multiple states of microglia activation and microglia loss in chronic lesions. Acute axonal damage is a pathognomonic and shared feature of these diseases. Data from the first funding period obtained by unbiased spatial transcriptome analysis in human central nervous system (CNS) tissue revealed distinct transcriptomic clusters identifying lesion areas with abundant or little neuroaxonal damage in the diseases. In this proposal, we plan to extend these findings to cellularly resolved spatial information in order to define glia cell networks operating in the distinct lesion areas. Thereby, we strive to identify the key cellular and molecular mediators underlying tissue damage in CSF1R-LE, CALD, and MS. In addition, we will test which key regulated molecules in our humanized mouse models of microglia deficiency expedite lesion formation and thus qualify for therapeutic targets. Last but not least our proposal aims at improving patient care, in particular by identifying novel and early means of CALD lesion detection, by optimizing hematopoetic stem cell transplantation, and by identifying biomarkers correlating to disease evolution and transplant success.
DFG Programme
Priority Programmes
