Principal Investigator/Program Director (Last, first, middle): Kartje, Gwendolyn, L RESEARCH &RELATED Other Project Information 1. * Are Human Subjects Involved? m Yes l No 1.a. If YES to Human Subjects Is the IRB review Pending? m Yes m No IRB Approval Date: Exemption Number: 1 2 3 4 5 6 Human Subject Assurance Number 2. * Are Vertebrate Animals Used? l Yes m No 2.a. If YES to Vertebrate Animals Is the IACUC review Pending? l Yes m No IACUC Approval Date: Animal Welfare Assurance Number A-3117-01 3. * Is proprietary/privileged information m Yes l No included in the application? 4.a.* Does this project have an actual or potential impact on m Yes l No the environment? 4.b. If yes, please explain: 4.c. If this project has an actual or potential impact on the environment, has an exemption been authorized or an environmental assessment (EA) or environmental impact statement (EIS) been performed? m Yes m No 4.d. If yes, please explain: 5.a.* Does this project involve activities outside the U.S. or l Yes m No partnership with International Collaborators? 5.b. If yes, identify countries: Switzerland 5.c. Optional Explanation: Professor Schwab is our long time collaborator 6. * Project Summary/Abstract 3700-ProjectSummary.pdf Mime Type: application/pdf 7. * Project Narrative 2916-Relevance.pdf Mime Type: application/pdf 8. Bibliography &References Cited 4695-Literaturecited.pdf Mime Type: application/pdf 9. Facilities &Other Resources 9224-RESOURCES.pdf Mime Type: application/pdf 10. Equipment Tracking Number: Other Information Page 5 OMB Number: 4040-0001 Expiration Date: 04/30/2008 Principal Investigator/Program Director (Last, first, middle): Kartje, Gwendolyn, L Project summary Stroke is a devastating disorder that leads to neuronal death and neurologic disability. The brain's inherent ability to form new neuronal connections and restore lost function can be enhanced by neutralizing the inhibitory nature of the adult CNS through antibody therapy targeting the protein Nogo-A. We have shown that anti-Nogo-A immunotherapy results in neuronal plasticity and functional recovery after ischemic stroke in adult rats. A better understanding of the mechanism underlying anti-Nogo-A immunotherapy would lead to improved therapeutic approaches for clinical use. Additionally, since stroke is more prevalent in the aged, ischemic stroke is best studied in a model which incorporates the aged animal, as we propose here. We hypothesize that interfering with the growth inhibitory protein Nogo-A induces specific genomic changes and enhances functional recovery after stroke by increasing axonal and dendritic plasticity in brain regions important for sensorimotor function. We will test our hypothesis in the following specific aims:
Specific aim #1 - Determine whether anti-Nogo-A immunotherapy after stroke results in increased axonal and dendritic plasticity in the aged rat. We will also determine the appropriate treatment time for therapy, and examine genomic changes that occur after stroke and anti-Nogo-A therapy in order to better understand the other important gene products important for stroke recovery in our model.
Specific aim #2 - Determine whether contralesional forelimb cortex mediates recovery after stroke and anti-Nogo-A immunotherapy. We will use both large and small stroke volumes to determine the effects of lesion size on mechanisms of stroke recovery and also use intracortical microstimulation to map the remaining cortical tissue by examining evoked forelimb movements.
Specific aim #3 - Determine whether global or oligodendrocyte-specific Nogo-A knockout mice demonstrate spontaneous neuroplasticity after ischemic stroke, and also perform genomic analysis to determine other important gene products for plasticity after stroke. The results of these studies will lead to new therapeutic approaches to return lost function to patients suffering from ischemic as well as other causes of brain damage by giving new insight into repair mechanisms in the aged brain, and lead to appropriate design for the translation into clinical trials using anti-Nogo-A immunotherapy after stroke. Project Description Page 6
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