Our laboratory seeks to explain how axons are guided to the correct sites during development and to describe the extent to which axonal connectivity is fixed or malleable in the adult. Our previous work has identified the myelin-derived inhibitory protein, Nogo-A, and an axonal Nogo-66 Receptor (NgR1) as inhibitors of axonal regeneration after adult brain or spinal injury. The natural function of this system is to limit adult brain plasticity and to reduce the risk of psychiatric disease. We are exploring the physiological role of NgR in brain plasticity by imaging intact neurons in living animals with a two-photon microscope through windows in the skull. We are also developing blockers of this system using structural biology, mutagenesis and high-throughput screening methods. Such antagonists are now shown to exhibit dramatic regenerative efficacy in the treatment of CNS injury, including spinal cord trauma and stroke.
We have initiated studies in the neuronal degeneration in Alzheimer’s Disease (AD) and Frontotemporal Dementia (FTD). In both of these diseases, specific extracellular peptides are implicated in the disease process, but the neuronal receptor which mediates the peptide effect is not known. Using expression cloning methods, we have identified high affinity binding sites for the Aß oligomers of AD and the progranulin/granulin peptides of FTD. We are characterizing the significance and receptor-type action of these high affinity binding sites for Aß and Progranulin.
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