This supplemental application requests funds to expand significantly the scope of our original application NS31768 funded April 1,2002. Work sponsored by the grant explores the roles of growth factor signaling mediators in developmental and regenerative axon growth.
In Aim 2 of the original grant, we proposed to generate a DRG specific B-Raf null mouse. Increasingly, it is apparent that a more comprehensive analysis of Raf and ERK family members would markedly enhance the impact of our proposal. The Raf/ERK pathway occupies a central position in mediating receptor tyrosine kinase signaling and is expected to be critical in mediating the functions of neurotrophins and other neuronal growth factors throughout the nervous system. The mouse gene targeting studies performed to date have not providing definitive information about requirements for Rafs and ERKs in nervous system development and function, in some cases because of early lethality of null mice, and some cases because of possible """"""""compensatory"""""""" effects of closely related family members. Rapid progress in generating floxed alleles using BAC """"""""recombineering"""""""" now allows us to target multiple Raf and ERK family members thought to be involved in neurotrophin signaling. We propose a convenient strategy for generating conventional and inducible DRG-specific mutations in B-Raf, C-Raf, ERK2 and ERK5, and for incorporating DRG-specific axonal reporters for convenient visualization of developmental and regenerative sensory axon growth. The supplement requests the funds to support necessary cage costs, PCR genotyping, and colony maintenance. Because of the general importance of neurotrophin signaling to neural development and function, we anticipate that the floxed allele mice we propose to generate will be of interest to other neuroscientists. We will ship any of these lines to investigators who request them at the time of the first publication. Defining the signaling mediators of regenerative axon growth will critically inform strategies to promote regrowth of axons after spinal cord injuries in humans. ? ?
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