Mark T. Milner, PhD

Despite decades of Multiple Sclerosis (MS) research, progressive neurodegeneration and neural circuit disassembly leading to permanent disability still pose an urgent unmet clinical need. Our previous work revealed that reactive microglia eliminate synapses, driving visual circuit dysfunction in MS. My new preliminary data highlights decreased synaptic densities exclusively surrounding reactive disease-associated microglia (DAM). Thus, I hypothesize that the DAM phenotype is required for synaptic loss in demyelinating disease. Recent work has revealed spleen tyrosine kinase (SYK) as a master regulator facilitating the transition of microglia into DAM. Here, I will genetically and pharmacologically target DAM regulatory factor SYK to impair the DAM transition in mouse and human microglia and analyze reactivity, and synaptic circuit structure and function. This work will reveal DAM as a novel therapeutic target to protect against progressive neurodegeneration and dysfunction in MS.