Project Details
Projekt
A novel in vivo human-mouse chimeric brain model to study human microglia specification and contributions to neuropsychiatric disease
Applicants
Professor Dr. Josef Priller; Dr. Simon Schäfer
Subject Area
Molecular Biology and Physiology of Neurons and Glial Cells
Experimental Models for the Understanding of Nervous System Diseases
Experimental Models for the Understanding of Nervous System Diseases
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 500300695
To understand and study human microglia function in health and disease, there is an unmet need for human cell-based models that feature functionally mature cells operating within a physiologically-relevant environment. This project will set out to characterize a novel humanized model system to advance the study of human-specific microglia states and functions in health and disease. To achieve this, we have developed an approach that mimics the colonization of human brain organoids through human erythromyeloid progenitors and capitalizes on our ability to graft these units into a rodent host for vascularization. Taking advantage of this approach, we shall first comprehensively profile and compare microglia states in our humanized neuro-immune models to human brain tissue using single cell transcriptomics, immunohistochemistry and mass cytometry. We will then aim to generate gender-specific neuro-immune models to assess environment-specific and intrinsic factors that contribute to sexual dimorphism of microglia in humans. By combining intravital microscopy, high-throughput molecular profiling and advanced immunohistochemistry, we aim to focus in particular on those microglia states and functions that shape early prenatal stages of human brain development. We shall further use this model to assess if sex differences in endogenous microglia functions or the brain environment may in part be responsible for sexual dimorphic responses under specific pathological conditions. By taking advantage of the modularity of this technology, we will generate human patient-specific models of Rett syndrome, an X-linked autism spectrum disorder characterized by the mutation of the methyl CpG-binding protein-2 (MeCP2), in order to interrogate the ability of our novel system to recapitulate human-specific aspects of the disorder.In summary, the suggested experiments will allow us to study the context-specific complexity of human microglia states and function and enable us to reveal the cellular and molecular mechanisms that contribute to their sexual dimorphic behavior in healthy and diseased brains. An in-depth assessment of both, human microglia and the surrounding cells that make up the human brain environment, will give us the unprecedented opportunity to investigate human-specific aspects of the dynamic interactions of microglia with neurons, macroglia and neurovascular cells. Our team is uniquely suited to undertake these novel and ground-breaking research endeavours, demonstrating a long-standing line of expertise with human disease models, organoid- and stem cell-based technologies (Dr. Simon Schäfer) as well as single-cell analysis approaches to characterize human microglia biology (Prof. Josef Priller). For the DFG priority programme 2395, we envision to contribute to an exceptionally collaborative research initiative, allowing us to establish a novel human model system for studying human microglia states and functions in health and disease.
DFG Programme
Priority Programmes
