Nerve damage as a result of stroke, trauma, or neurodegenerative disease is a major source of morbidity and mortality. The objective of this proposal is to examine the regulation of molecular events that lead to successful nerve regeneration in peripheral nerves so that rational therapies for nerve injury can be devised. Previous studies have demonstrated that distal nerve injury stimulates sustained alterations in mRNA levels of neuronal proteins which include cytoplasmic and axonally-- transported structural and regulatory proteins. This proposal hypothesizes that the response to nerve injured is initiated through known and novel immediate early genes (IEGs) produced by both neuronal and non-neuronal cells. This hypothesis will be investigated by Northern blot analysis and in situ mRNA hybridizations of selected known IEGs in the dorsal root ganglia of injury and control sciatic nerves in order to demonstrate and establish a time-course of IEG expression. Once the time of maximal IEG expression is determined, additional IEGs relevant to nerve regeneration will be identified by molecular cloning from subtracted cDNA libraries prepared from the dorsal root ganglia of normal and regenerating sciatic nerves. This proposal will also investigate the role of the putative retrograde signal which transduces axon injury to stimulate the neuronal perikarya to express the appropriate proteins to effect regeneration. Since IEG expression is often quite transient, the rate of retrograde signal transduction can be accurately determined from the distance between the site of nerve injury and the DRG along with the time of maximal expression of the IEGs. Furthermore, by characterizing the genomic structure of nerve regeneration associated IEGs, common enhancer sequences can be identified and used as probes to isolate specific DNA binding proteins that initiate the neuron's response to nerve injury. Proteins identified in this fashion should include the retrogade signal or its transducer. As part of an ongoing collaboration, the proposed project will determine the cellular location for the mRNA of the recently described SR 13 protein whose mRNA is rapidly down-regulated in non-neuronal cells following nerve injury. The SR 13 protein is both a novel myelin protein and a homologue to the growth-arrest specific (gas) gene, gas-3. Since both gas genes and the anti-oncogenes, p53 and the retinoblastoma susceptibility gene (RB), have been hypothesized to suppress cell proliferation through interaction with IEGs, this proposal will also examine the possible interaction of SR13 with the IEGs of nerve sheath cells following nerve injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS001559-02
Application #
3084705
Study Section
NST-2 Subcommittee (NST)
Project Start
1992-04-01
Project End
1997-03-31
Budget Start
1993-04-01
Budget End
1994-03-31
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Stanford University
Department
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Pareek, S; Notterpek, L; Snipes, G J et al. (1997) Neurons promote the translocation of peripheral myelin protein 22 into myelin. J Neurosci 17:7754-62
Haney, C; Snipes, G J; Shooter, E M et al. (1996) Ultrastructural distribution of PMP22 in Charcot-Marie-Tooth disease type 1A. J Neuropathol Exp Neurol 55:290-9
Snipes, G J; Suter, U; Welcher, A A et al. (1995) The molecular basis of the neuropathies of mouse and human. Prog Brain Res 105:319-25
Suter, U; Snipes, G J; Schoener-Scott, R et al. (1994) Regulation of tissue-specific expression of alternative peripheral myelin protein-22 (PMP22) gene transcripts by two promoters. J Biol Chem 269:25795-808
Snipes, G J; Suter, U; Shooter, E M (1993) Human peripheral myelin protein-22 carries the L2/HNK-1 carbohydrate adhesion epitope. J Neurochem 61:1961-4
Snipes, G J; Suter, U; Shooter, E M (1993) The genetics of myelin. Curr Opin Neurobiol 3:694-702
Suter, U; Welcher, A A; Snipes, G J (1993) Progress in the molecular understanding of hereditary peripheral neuropathies reveals new insights into the biology of the peripheral nervous system. Trends Neurosci 16:50-6