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Jeffrey Milbrandt, M.D., Ph.D.
James S. McDonnell Professor and Head
Pathology and Immunology
Molecular Genetics and Genomics Program
Developmental, Regenerative and Stem Cell Biology Program
Molecular Cell Biology Program
MRB - McKinley Research Building, Room 6306
functional genomics, metabolism, mitochondria, diabetic neuropathy, neurodegeneration, transcriptional networks, Alzheimer’s disease, Schwann cell
Axonal degeneration, regulation of myelination, neuronal energetics and mitochondrial function in neuropathy and neurodegenerative disease
Axonal degeneration is a major component of many neurodegenerative diseases, including peripheral neuropathy, Alzheimer’s disease, ALS, and Parkinson’s disease. The central mechanism behind the axonal pathology in these disorders is the activation of a self-destructive program that eliminates damaged or unhealthy axons. We have discovered that enzymes involved in the synthesis (Nmnat) or consumption (SARM1) of NAD are crucial components of the axon destruction pathway. Activation of this destructive pathway can occur via direct assaults on the neuron/axon or, indirectly, through interruption of axonal support by glial cells. This indirect path is particularly apparent in the periphery, where disrupted Schwann cell metabolism leads to axonal degeneration and the development of neuropathy. We are further characterizing the intrinsic axon self-destructive pathways in hopes of finding methods to block its function, as well as studying how disruption of glial cell metabolism contributes to development of neurodegenerative disorders.
CRISPR/Cas9 genome engineering, single-cell sequencing technologies, and iPSC methodologies are revolutionizing many aspects of biomedical science. Together, they allow for the rapid assessment of the impact of disease-associated variants on disease-relevant cell types. We are adapting these advances to study neuronal and glial function, with initial experiments aimed at 1) understanding the role of dopaminergic system in drug addiction and neuropsychiatric disorders; 2) assessing the functional impact of gene variants associated with autism and intellectual disabilities; and, 3) identifying components that regulate axon/Schwann cell interactions and are important in diabetic neuropathy. We are pursuing these studies using specifically modified mouse models as well as patient-derived iPSCs. Other projects are aimed at improving the trans-differentiation of fibroblasts and iPSCs into specific glial and neuronal subtypes. New approaches aimed at using Cas9 technology to perform in vivo screens of nervous system function are being pursued using AAV-mediated delivery of gRNAs.
Last Updated: 4/10/2017 2:09:25 PM