Project Details
Projekt
Elucidating sex-specific and disease-associated human microglia phenotypes and their contribution to Rett Syndrome
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
This project seeks to uncover how the brain’s resident immune cells, known as microglia, influence human brain development and contribute to neuropsychiatric disorders such as Rett Syndrome. Microglia play a crucial role in maintaining brain health by adapting to changes in their environment. Previous research has established a strong link between immune activation and neurodevelopmental disorders. However, it remains unclear how these responses differ between males and females, and if such differences might shape the risk for neuropsychiatric disorders. Leveraging a novel organoid-based in vivo platform that we established during the last funding period, this project will explore how early immune challenges differentially impact on microglia in male and female brains during critical stages of development. Using advanced tools such as intravital microscopy, high-throughput molecular profiling, and computational methods to infer cellular crosstalk, we will investigate whether these immune responses result in divergent developmental trajectories and distinct disease risks between sexes. Our aim is to determine how early immune challenges affect microglial function in males and females, potentially providing insights into why certain neurodevelopmental and neuropsychiatric disorders present differently in each sex. Finally, we will investigate how mutations in the MECP2 gene associated with Rett Syndrome – a neuropsychiatric disorder that primarily affects females – alter microglial behaviour, disturb crosstalk with neural cells and contribute to disease progression. By using patient-derived cells and spatial transcriptomics to create personalized brain models, we hope to better understand how disease-associated microglia contribute to pathology in humans. These models will allow us to explore how both genetic mutations and environmental factors interact to shape disease outcomes. Ultimately, this research will provide critical insights into sex-specific differences in human microglia and their roles in neurodevelopmental and neuropsychiatric disorders. By elucidating these mechanisms, we aim to open new avenues for therapeutic interventions, tailored to account for sex differences in disease susceptibility and progression.
DFG Programme
Priority Programmes
