Centre for Neuroscience - Theses
Permanent URI for this collection
Search Results
1 - 1 of 1
-
ItemEarly gene expression following peripheral nerve injury( 2011)The mammalian nervous system regulates the response to both internal and external stimuli, thus any injury can have profound effects leading to considerable disability. Although advancements in surgical technique have facilitated significant improvements in the treatment of peripheral nerve injuries, there have been few recent innovations leading to further addditional improvement in functional outcome. As such, attention has now turned to understanding the inherent cellular and molecular mechanisms that underlie the regeneration response. This thesis will attempt to improve the understanding of these processes that are activated within the first 24 hours following peripheral nerve injury. It is proposed that discernable patterns can be elucidated to enable a deeper understanding of the biological processes that are modulated following traumatic neuronal injury, and appropriate therapeutic targets could be developed to improve the functional outcome. The rodent sciatic model was used to facilitate whole genome microarray analysis of gene expression profile of the dorsal root ganglion (DRG) following axonal injury. During ultra-early temporal analysis (less than 24 hours after injury), differential gene expression occurred within four hours and peaked at 24 hours after axotomy, with 2,022 probe-sets determined to be significant. One biological pathway modulate was the mitogen-activated protein kinase (MAPK) cascade that is fundamental for neuronal survival and regeneration. As the pattern of change in mRNA cannot be directly correlated with the biological function of related proteins, phosphorylation of two effector proteins of the MAPK cascade at 4 and 24 hours, c-Jun (76.8+/-2.7%; p<0.05 and 80.6+/-4.1%; p<0.01) and ATF2 (72.7+/-1.2%, p<0.01 and 82.2+/-1.4%, p<0.001) were studied and found to be modulated in a similar fashion iv within the neuronal and satellite glial cell (SGC) population respectfully. In addition, there was evidence of SGC proliferation within the first 24 hours after axotomy (0.2+/-0.01, p<0.05 and 0.2+/-0.01, p<0.005). At 24 hours post-injury, differential gene expression was found to be proportional to the severity of axonal injury (2,060 significant probe-sets). Similarly, following crush injury and axotomy, the neuronal phosphorylation of c-Jun (77.9+/-3.2%; p<0.001 and 84.6+/-4.3%; p<0.001), SGC phosphorylation of ATF2 (76.6+/-8.6%, p<0.001 and 78.6+/-6.2%, p<0.001) and SGC proliferation (0.13+/-0.01, p<0.01 and 0.14+/-0.01, p<0.001) was discovered to be also proportional to the severity of axonal injury. Following crush injury and axotomy, the glucocorticoid dexamethasone was administered and found to induce the neuronal phosphorylation of c-Jun while inhibiting the SGC phosphorylation of ATF2 and proliferation at 24 hours post-injury. What remains to be clarified is the functional repercussions of the effect of dexamethasone on these proteins and SGCs proliferation. It is proposed that the understanding of the biological processes that occur during the neuronal response to axonal injury gained within this thesis, provides the opportunity to potentially target biological processes that might improve functional outcomes following peripheral nerve injury. This project provides the platform for future studies to test means of neuro-protection following axonal injury.