Enhanced expression of the transcription factor Sox11 was identified in developing sensory neurons of trigeminal and dorsal root ganglia of transgenic mice that overexpress neurotrophic growth factors in the skin. This expression suggested that Sox11 transcriptionally regulate genes involved in the enhanced neuron survival and axon projections exhibited by cutaneous sensory neurons in these animals. In adult DRG Sox11 was expressed at a low level but showed a significant increase following peripheral nerve crush. The high level of Sox11 expression during development and following adult neuron injury suggests Sox11 modulates a specific set of genes that have essential roles in neuron survival and axon growth. The experiments of this proposal will begin to define putative targets of Sox11 action and determine how its expression in adult neurons modulates their survival, axonal growth and response properties.
Three specific aims are proposed.
Aim 1 will use luciferase reporter assays to test if identified target genes involved in survival and axon growth are modulated by Sox11 expression.
Aim 2 will examine if the level of Sox11 expression in DRG cultures or following in vivo nerve injury correlates with the rate and quality of anatomical and functional recovery. In these studies we will manipulate Sox11 level using two approaches. To decrease expression in DRG neurons we will use a RNAi approach. To increase expression of Sox11 we will use non-replicating, neurotropic HSV viral vectors. Changes in Sox11 level may alter expression of genes involved in afferent sensitivity and pain signaling which could lead to behavioral sensitivity.
Aim 3 will test this possibility by measuring behavioral responses to applied thermal and mechanical stimuli. Relevance to Public Health: Impaired recovery following nerve injury can have significant effects on the quality of life and productivity of an individual due to abnormal nerve function or persistent pain following injury. Improved understanding of the cellular and molecular mechanisms that underlie survival and functional recovery of neurons following traumatic injury is required for design of effective strategies for recovery.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS059003-02
Application #
7547001
Study Section
Special Emphasis Panel (ZRG1-IFCN-K (02))
Program Officer
Kleitman, Naomi
Project Start
2008-01-01
Project End
2012-11-30
Budget Start
2008-12-01
Budget End
2009-11-30
Support Year
2
Fiscal Year
2009
Total Cost
$331,406
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Salerno, K M; Jing, X; Diges, C M et al. (2013) TRAF family member-associated NF-kappa B activator (TANK) expression increases in injured sensory neurons and is transcriptionally regulated by Sox11. Neuroscience 231:28-37
Salerno, Kathleen M; Jing, Xiaotang; Diges, Charlotte M et al. (2012) Sox11 modulates brain-derived neurotrophic factor expression in an exon promoter-specific manner. J Neurosci Res 90:1011-9
Jing, Xiaotang; Wang, Ting; Huang, Shaohua et al. (2012) The transcription factor Sox11 promotes nerve regeneration through activation of the regeneration-associated gene Sprr1a. Exp Neurol 233:221-32
Henson, Brian J; Zhu, Wan; Hardaway, Kelsey et al. (2012) Transcriptional and post-transcriptional regulation of SPAST, the gene most frequently mutated in hereditary spastic paraplegia. PLoS One 7:e36505
Jankowski, Michael P; McIlwrath, Sabrina L; Jing, Xiaotang et al. (2009) Sox11 transcription factor modulates peripheral nerve regeneration in adult mice. Brain Res 1256:43-54
Goss, J R; Gold, M S; Glorioso, J C (2009) HSV vector-mediated modification of primary nociceptor afferents: an approach to inhibit chronic pain. Gene Ther 16:493-501
Jankowski, Michael P; Lawson, Jeffrey J; McIlwrath, Sabrina L et al. (2009) Sensitization of cutaneous nociceptors after nerve transection and regeneration: possible role of target-derived neurotrophic factor signaling. J Neurosci 29:1636-47
Glorioso, Joseph C; Fink, David J (2009) Herpes vector-mediated gene transfer in the treatment of chronic pain. Mol Ther 17:13-8