SPP 2395:  Local and peripheral drivers of microglial diversity and function

• Subject Area: Medicine
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 461101128

In the coming years, the research field will advance beyond a simple concept of disease-associated microglia, or homeostasis-associated microglia. Sophisticated transcriptomic and transgene technologies will be combined with cutting edge in vivo imaging methods to link RNA and Protein expression profiles to distinct microglia function. In addition, analysis of big data and in silico modelling will be further employed by pre-clinical studies improving efficacy and transparency of our research activities. At the same time, bioethical aspects and quality and data management will get integrated to a greater extend into this priority program. Moreover, the current situation calls to investigate the response of microglia against viruses such as COVID-19 and its acute and long-term consequences for brain health. Therefore, it is timely to build a nation-wide, international competitive, interdisciplinary consortium and launch a priority program dedicated to investigate microglia biology.The program aims to address the following three main questions:1. Which local cues determine the microglia state? 2. How does the peripheral immune status (e.g. viral infections) modulate the microglia state and phenotype during development and ageing?3. How much of the mouse work is reflected in human diseases and how can we improve the pre-clinical models? In order to answer these questions, we need to evaluate and assimilate current data and knowledge, use cutting edge methods to visualize and manipulate microglia and integrate the peripheral-brain immune axis into our future research. Taken together, we propose the following aims and deliverables for the priority program:-Build a nation-wide database integrating OMICS, structural and functional data. -Add sex/gender as a variable into the database.-Identify local cues that shape microglia function and phenotype. -Use these data for in silico and mathematical modelling to identify therapeutic targets. -Investigate identified targets in animal models and humans.

• DFG Programme: Priority Programmes
• International Connection: Austria, Finland, Israel, United Kingdom

Projects

• A humanized mouse model to analyse the age-dependent impact of gut microbiota on microglial diversity in the brain (Applicants Frahm, Christiane ;  Kaleta, Christoph ;  Schmeer, Ph.D., Christian )
• A novel in vivo human-mouse chimeric brain model to study human microglia specification and contributions to neuropsychiatric disease (Applicants Priller, Josef ;  Schäfer, Simon )
• Aberrant microglia function as driver of neuroaxonal degeneration in diseases of the white matter (Applicants Bergner, Caroline ;  Nessler, Stefan ;  Stadelmann-Nessler, Christine )
• Coordination Funds (Applicant Wolf, Susanne A. )
• Desialylation as trigger of microglia responses in the aging and degenerating retina (Applicants Langmann, Thomas ;  Neumann, Harald )
• Elucidating the role of activated microglia in sculpting neuronal circuits after respiratory viral infections (Applicants Hosseini, Shirin ;  Korte, Martin )
• Epigenomic states of microglia driving central nervous system repair in humans (Applicant Ludwig, Leif )
• MacTrac – Tracking spatio-temporal trajectories of macrophage subtypes in inflammatory demyelination (Applicants Saez-Rodriguez, Julio ;  Schirmer, Lucas )
• Microglial IL-10 expression and the impact of CNS-wide microglia responses on higher brain function (Applicant Jung, Ph.D., Steffen )
• Microglial immunosurveillance of oncogenic IDH – (CONVINCE-IDH) (Applicant Platten, Michael )
• Microglial lipid metabolism during physiological and pathological conditions (Applicant Mildner, Ph.D., Alexander )
• Microglial-neuronal interaction in the recovery phase of cerebral ischemia (Applicants Magnus, Tim ;  Oertner, Thomas )
• Multidimensional analysis and therapeutic targeting of microglia fostering brain tumor relapse (Applicants Flüh, Charlotte ;  Glass, Rainer )
• Myeloid cell diversity and ischemic stroke (Applicant Gertz, Karen )
• T cells as modulators of microglial reactivity in Alzheimer’s disease (Applicants Liesz, Arthur ;  Tahirovic, Ph.D., Sabina )
• The continuum of microglial subpopulations to functional changes in multiple sclerosis (Applicant Böttcher, Chotima )
• The cytoskeleton as a signaling node that contributes to microglia activation and diversity (Applicants Bradke, Frank ;  Halle, Annett )
• The deubiquitinating enzymes CYLD and A20 as gate keepers of central nervous system homeostasis (Applicant Waisman, Ari )
• The role of microglial cytoskeleton proteins ADF/Cfl1 in learning and memory (Applicants Crux-Daseking, Sophie ;  Fuhrmann, Martin )

• Spokesperson: Privatdozentin Dr. Susanne A. Wolf