Our research focuses on Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease. ALS is characterized by progressive degeneration of motor neurons, the final common pathway neurons that drive the skeletal musculature. We are interested in two key questions:
Why are some motor neurons selectively vulnerable in ALS?
Degeneration of motor neurons in ALS is not uniform. Certain motor neurons are resistant to degeneration (e.g., oculomotor neurons). Even within vulnerable motor pools, there is preferential death of larger motor neurons. We are investigating the cellular and molecular signatures of vulnerable versus resistant motor neurons. Our working hypothesis is that identifying cell-specific markers of disease resistance can aid the design of therapeutic strategies that can promote disease resistance.
Is ALS neural circuit specific?
Although ALS is characterized as a motor neuron disease, increasing evidence suggest abnormal synaptic inputs and astrocyte involvement, early during disease development. Secondly, viewing ALS as a neuromuscular disease, it is further imperative that muscle stretch reflex circuits of vulnerable musculature are abnormal. We are therefore investigating circuit-specific abnormalities involving sensorimotor components to develop a spatiotemporal theory of disease development in ALS. Targeting such neural circuits using pharmacotherapy, regenerative approaches and neural engineering-based rehabilitative strategies could help delay the disease progression. Circuit-specific markers of disease development can aid biomarker discovery in ALS.
These mechanistic investigations use transgenic mouse models and diverse tools and techniques including:
- Patch-clamp and dynamic-clamp electrophysiology
- Computational and mathematical modeling
- Systems biology
- Live cell imaging and image processing
- Cell specific immunoassays for protein quantification
- Various histological methods (H&E, Immunohistochemistry, Nissl staining)
We are grateful for the generous support from:
- Dr. Scott Chandler Lab (Integrative Biology and Physiology)
- Dr. Martina Wiedau-Pazos Lab (Neurology)
- Dr. Xia Yang Lab (Integrative Biology and Physiology)
- Dr. Igor Spigelman Lab (Section of Oral Biology, Dentistry)
- Dr. Riccardo Olcese Lab (Anesthesiology and Perioperative Medicine, Physiology)
- Dr. Michael Levine Lab (Department of Psychiatry and Biobehavioral Sciences)