I, Dr. Guo-rong Zhang, have had a remarkable journey. I am from a small agricultural town about a day's drive south of Beijing, China. I worked my way up through the Chinese system, first at a provincial University and then in Beijing, obtaining both the M.D. and Ph.D. I then joined Dr. Geller's Laboratory at the W. Roxbury VA Hospital/Harvard Med. Schl. In July 2004, I was promoted to Instructor, a faculty level position. In Feb. 2004,1 received permanent residency status. I am intent on having an academic career in the US. I am skilled in neurosurgery and neuroanatomy, and have a broad overall knowledge of neuroscience. This proposal will provide training in molecular biology, virology, neuronal physiology, and learning and memory. Training includes coursework and a research program, emphasizing the new areas for me. This training should enable me to become an independent scientist and obtain NIH research grant (R01) support. Cognitive deficits are caused by aging, specific neurodegenerative diseases, stroke, and other conditions. No effective treatments are available. Gene therapy has tremendous potential for treating specific cognitive deficits. Learning theories hypothesize that neurons in a specific circuit use specific signaling pathways to modify synaptic strengths, thereby mediating learning. Thus, altering the physiology of a small group of neurons can potentiate a specific circuit and enhance learning, providing a treatment for cognitive deficits. I have established that genetic activation of protein kinase C (PKC) pathways in small groups of rat postrhinal cortex neurons enhances learning of visual object discriminations. PKC pathways were activated in several hundred predominantly glutamatergic and GABAergic neurons (using a Herpes Simplex Virus (HSV-1) vector that expresses a constitutively active PKC). Also, I showed that activating PKC pathways in small groups of hippocampal dentate granule neurons enhances learning of an auditory reversal discrimination, and, in aged rats, corrects deficits in a spatial learning. The long-term goal of this proposal is to develop a gene therapy treatment for cognitive deficits. The first specific aim will characterize correction of cognitive deficits in aged rats following activation of PKC pathways in small groups of hippocampal or postrhinal cortex neurons. The second specific aim will determine how long the recombinant PKC must be expressed to correct the learning deficits. ? ? ?
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