Recombinant adeno-associated viral (rAAV) vectors are frequently used for gene delivery to the central nervous system and are capable of transducing neurons and glia in the rodent brain. In collaboration with Dr. Ania Majewska (U Rochester), we compared AAV serotype transduction in mouse cortex using an AAV vector expressing the green fluorescent protein. We identified serotypes capable of transducing neurons in mouse cortex and labeling them extensively to the endpoint of identifying dendritic spines. These neurons could be imaged in vivo using two photon microscopy and the same neurons could be imaged over several days. This establishes a method to monitor changes in cortical neuron morphology during development and in response to trauma, disease or drugs of abuse. Our results were published this year. In collaboration with Dr. Nigel Grieg (NIA), we have investigated the neuroprotective effects of activating the Glucagon-like peptide-1 receptor (GLP-1R). This year we published the protective effects of GLP1R receptor agonists (GLP-1 and exendin-4) against neurodegeneration in rodent models of stroke and Parkinsons disease and the results. We are currently developing an AAV vector expressing exendin-4 for further exploring therapeutic strategies including inducible expression. In addition, we are identifying methods of delivery AAV via the ventricular system for gene delivery of Exe-4 in several models of neurodegeneration including stroke, Alzheimers and ALS. This work in ongoing. As part of a collaboration on a primary project of Dr. Barry Hoffer (NIDA), we are examining the neuroprotective effects of conserved dopaminergic neurotrophic factor (CDNF) in a mouse model of Parkinsons disease. We are examining whether CDNF protein or an AAV-CDNF can confer neuroprotection and neuroregeneration in against neurotoxicity caused by MPTP. This work is ongoing. We are currently investigating the mechanisms of Mesencephalic astrocyte-derived neurotrophic factor (MANF)-mediated neuroprotection in a rodent model of stroke. Using an AAV vector expressing MANF, we can reduce ischemic brain injury. Using this model and evidence that MANF may be a mediator of the unfolded protein response (UPR) to endoplasmic reticulum stress, we are examining the molecular mechanism of MANF neuroprotection. We are also conducting cell culture experiments and C. elegans experiments to address the protective mechanisms of MANF as it relates to its function in ER stress. The phenomenon of ER stress occurs in many diseases beyond neurodegenerative and understanding its role may lead to broader therapeutic strategies. This work is ongoing.
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