Neural Repair & Neuro-Degeneration
Neurological injury frequently interrupts connections while sparing nerve cells themselves. Spinal Cord Injury (SCI) is the epitome of a disconnection syndrome, in which surviving neural tissue fails to function due to lost communication above and below 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 chronic in vivo imaging of neuronal cennections, genetic alteration of mice and induction of surgical lesions resembling clinical SCI and Stroke. In particular, we have found that the Nogo Receptor (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 (cell surface binding of Aß oligomers in green to neurons in red is shown at left). We utilize receptor ligand binding assays, expression cloning, electrophysiology, mouse genetics and mouse behavior to study these pathways.
Our long term goal is to translate understanding of neurodegeneration and nerve fiber growth into therapeutic options for currently untreatable neurological diseases. Today, no medical intervention exists to promote neurological recovery after Spinal Cord Injury or Stroke. Existing therapies for degenerative diseases, such as Alzheimer's Disease, fail to alleviate, or even modify, the underlying pathophysiology. The goal of our mechanistic studies is to develop rational therapies for unmet Neurological need.