Peripheral nerve lesions (e.g. trauma, Herpes Zoster, diabetic and AIDs neuropathy) can lead to a loss of sensation as a result of the degeneration or death of primary sensory neurons in the dorsal root ganglion. This grant proposes to examine factors responsible for the survival and the loss of dorsal root ganglion neurons after peripheral axonal injury and after disruption in Schwann cell-axon signaling. This will be investigated by examining the cell survival roles of two genes, the small heat shock protein Hsp27 (Hsp27) and the peripheral benzodiazepine receptor (PBR), and by identifying those transcription factors responsible for the regulation of these genes.
Three Aims will be investigated: 1. Can Hsp 27 overexpression rescue DRG neurons from cell death after peripheral nerve injury in the neonate and adult mouse and does its survival role require its phosphorylation? 2. Does the upregulation of PBR after nerve injury play a role in sensory neuron survival in the mouse after injury or a disruption in Schwann cell-axon signaling? 3. What is the master molecular switch responsible for the induction of cell survival genes after nerve-injury? Gain and loss of function approaches in vivo and in vitro will be used to study the contribution of Hsp27 and PBR to sensory neuron survival and injury-induced death. A cluster analysis of gene expression profiles obtained from high-density oligonucleotide microarrays will be used to identify genes regulated coordinately with Hsp27 and PBR and common consensus sites on their promoter regions. The major hypothesis to be tested is that certain transcription factors control cell survival of DRG neurons after axonal injury by regulating the transcription of genes essential for neuronal survival. Absence of these intrinsic survival genes contributes to cell death after nerve injury/lesions.
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