Neural Repair and Neuro-Degeneration
Neurological injury frequently interrupts connections while sparing nerve cells. Spinal Cord Injury (SCI) is the epitome of a disconnection syndrome, in which surviving neural tissue fails to function due to lost communication at the level of injury. For the organism to regain function, new pathways must form by growth of cut or surviving nerve fibers. Unfortunately, the growth of axons and the rearrangement of brain circuitry are extremely limited in the adult brain and spinal cord.
We focus on understanding the molecular pathways that limit fiber growth and functional rewiring of neuronal circuits during health and disease. Axonal growth encompasses both neural plasticity and repair. Technically, we utilize genome-wide functional screening, chronic in vivo imaging of neuronal connections, genetic alteration of mice and induction of surgical lesions resembling clinical SCI and Stroke. In particular, we have found that the NogoReceptor (NgR1) pathway mediating myelin inhibition of axonal growth plays a role in titrating anatomical plasticity in the adult CNS.
In Alzheimer's Disease and several other neurodegenerative conditions, nerve cells are lost over time. Molecular contributors to this pathology have been discovered by genetic methods, but their mechanism of action has remained poorly understood. We have focused on defining the pathophysiological action of Amyloid-beta (Aß) peptide oligomers in Alzheimer's Disease, and on the role of secreted Progranulin in Fronto-Temporal Dementia. For both of these molecules, interaction with the specific receptors on the neuronal surface is crucial. We utilize receptor ligand binding assays, expression cloning, electrophysiology, genetics and mouse behavior to study these pathways. Interrupting an Aß oligomer signal transduction pharamacologically rescues synapses and memory function in Alzheimer's disease models. These novel approaches are being translated to clinical trials.
Alzheimer Disease; Axons; Dementia; Spinal Cord Injuries; Regenerative Medicine; Frontotemporal Dementia