The Department of Biomedicine
BBB webinar

BBB seminar: Mandana Hunter

Implications of the central nervous system immune response in a mouse model of sporadic ALS and other TDP-43 proteinopathies

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Mandana Hunter
Center for Neurodegenerative Disease Research (CNDR), Institute on Aging, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

Neuroinflammation is a core feature of neurodegenerative pathologies. In amyotrophic lateral sclerosis (ALS), neuroinflammation manifests as increased reactive microglia accompanied by elevated inflammatory cytokines in central nervous system (CNS) tissue, blood, and cerebrospinal fluid. As the principal neuroimmune cells, microglia perform roles in surveillance of the CNS microenvironment, preservation of neuronal homeostasis and defence against disease-related insults. The execution of such tasks demands plasticity of microglia, which alter their phenotypic properties via “microglial reactions” to external cues. During neurological insult, microglial reactions may initially be protective. However, the chronic nature of neurodegeneration elicits sustained inflammation that can result in a deleterious imbalance in microglial functions, leading to an exacerbation of the disease. Accordingly, there is substantial interest in therapeutic approaches to augmenting the salutary effects of microglia whilst antagonizing their pathological activities. Our prior work on microglial reactions in the rNLS8 mouse model of sporadic ALS has informed the hypothesis that pharmacological inhibition of the myeloid/microglial receptor tyrosine kinase AXL may be an exciting novel therapeutic approach for ALS. The proposed study seeks to execute preclinical pharmacokinetic/ pharmacodynamic (PK/PD), efficacy and mechanism-of-action studies utilizing the potent, selective, orally bioavailable, and brain-penetrant small molecule AXL inhibitor bemcentinib.

Chairperson: James Lorens, Department of Biomedicine