THIS IS A SHANNON AWARD PROVIDING PARTIAL SUPPORT FOR THE RESEARCH PROJECTS THAT FALL SHORT OF THE ASSIGNED INSTITUTE'S FUNDING RANGE BUT ARE IN THE MARGIN OF EXCELLENCE. THE SHANNON AWARD IS INTENDED TO PROVIDE SUPPORT TO TEST THE FEASIBILITY OF THE APPROACH; DEVELOP FURTHER TESTS AND REFINE RESEARCH TECHNIQUES; PERFORM SECONDARY ANALYSIS OR AVAILABLE DATA SETS; OR CONDUCT DISCRETE PROJECTS THAT CAN DEMONSTRATE THE PI'S RESEARCH CAPABILITIES OR LEND ADDITIONAL WEIGHT TO AN ALREADY MERITORIOUS APPLICATION. THE ABSTRACT BELOW IS TAKEN FROM THE ORIGINAL DOCUMENT SUBMITTED BY THE PRINCIPAL INVESTIGATOR. DESCRIPTION: (adapted from Applicant's Abstract) Peripheral nerve regeneration is essential to the restoration of muscle movement, touch sensation, and pain sensation in denervated or damaged tissues. Nerve regeneration, however, is not always successful. To knowledgeably optimize the regeneration process and enhance the success rate, it is essential to understand how genes encoding neuronal components that are key to successful regeneration are activated by nerve injury. The overall goals of the proposed studies are to determine how genes respond to peripheral nerve injury and to determine the importance of one of those genes to the process of nerve regeneration. These studies focus on a gene encoding a subunit of the intermediate filament cytoskeleton, the peripherin gene, the expression of which increases robustly after nerve injury. The proposed experiments will define specific subsequences in the peripherin gene that are required for this response and will reveal mechanisms by which peripherin mRNA increases in response to nerve injury. These nerve injury responses of peripherin will be defined initially by analyzing, in transgenic mice, the nerve injury response of peripherin transgenes that contain deletions in regions suspected to be essential. These regions then will be tested for their ability to confer nerve injury-responsiveness on a heterologous reporter gene. Subsequences in these regions will be further delineated by DNA mobility shift assays that compare the mobility of the subsequences in the presence of nuclear extracts from non-injured and injured neurons. To determine whether the nerve injury response sequences are found in other genes that are similarly activated after nerve injury, several genes within the Genbank database that contain these sequences will be selected and their expression will be tested in nerve-crush studies. Finally, the proposed studies seek to clearly define the requirement for the intermediate filament cytoskeleton during regeneration by determining whether unmyelinated axons that are depleted of the peripherin intermediate filament network in transgenic mice can grow new daughter axons after nerve injury. Identification of factors that bind to the conserved sequences and identification of components that are key to regeneration ultimately will permit enhancement of the regenerative process.
