Axon degeneration
Axonal degeneration is a characteristic feature of many peripheral neuropathies, including chemotherapy-induced neuropathy. We demonstrated that the tubulin inhibitor vincristine, a commonly used chemotherapeutic to treat many hematological and childhood cancers, exerts direct toxic effects on axons, whereas the proteasome-inhibitor bortezomib, indicated for treatment of multiple myeloma and amyloidosis, leads to axon degeneration via signals from the neuronal soma. We furthermore discovered that these chemo-therapeutics trigger distinct, upstream pathways, which then converge on activation of a core axon degeneration program consisting of nicotinamide mononucleotide NMNAT2, SARM1, and loss of NAD+. In collaboration with the DiAntiono/Milbrandt labs we developed SARM1 dominant-negatives that potently suppress SARM1 activation in vitro and in vivo. With these tools in hand, we now
- Investigate the therapeutic potential of AAV-mediated the SARM1 dominant-negative expression in rodent models of chemotherapy-induced neuropathy
- Develop further approaches to block the final common axon degeneration pathway selectively in peripheral somatosensory nerves.
- Determine effects of these treatments on metabolome, transcriptome, cancer progression and chemotherapy.
Neuron-glia interaction
Role of satellite glia cells in chemotherapy-induced neuropathy
Glial cells are essential to fine-tune circuit formation and play an essential role in the development and progression of many neurodegenerative diseases. Peripheral glia comprise Schwann- and satellite glial cells. Schwann cells wrap around axons, whereas satellite glial cells envelop the sensory neuronal soma, thereby forming a distinctive morphological and functional unit found nowhere else in the nervous system. This structure positions the satellite glial cells to have important roles in modulating the activity of neurons. Using advancing sequencing techniques, in vivo models of chemotherapy-induced neuropathy and multimodal imaging, we are interrogating the role of satellite glia cells in chemotherapy-induced neuropathy
Clinical research
Traditional medical treatments have been designed as a “one-size-fits-all” approach. While these treatments can be effective for some patients, they may not be for others. Using clinical data and tissue samples, our goal is to deepen our understanding of peripheral neuropathies in order to make diagnosis, treatment strategies, and prevention of peripheral neuropathies more personalized, predictive and precise. Integrating detailed histories and thorough examinations of neuropathy patients, with high resolution flow cytometry, genomic and proteomic data from the same patients, we strive to
- Define relevant disease endotypes
- Stratify patients with small fiber neuropathy based on phenotypic endotypes
- Develop reliable, clinically-accessible biomarkers of disease endotypes, progression and treatment response