Epigenetic modifications in axonal sprouting and regeneration following spinal cord injury
Funded in: 2013, 2014, 2015
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Problem: Limited regeneration capacity of the axons in the CNS
Target: Retrograde axonal signals that may influence epigenetic modifications
Goal: Enhancement of the axonal regeneration by targeting epigenetic mechanisms
So far the molecular regulation and the mechanisms that control the growth capacity of injured axons are not clearly understood. It is known that axonal sprouting as well as regeneration and functional recovery following spinal cord injury (SCI) is a restricted by the neuronal pro-regenerative gene expression within the neural cells Research of the last years proved that the gene expression program of a cell may be modulated by epigenetic mechanisms. This means that the gene itself is not changed but the decoding of the gene and translation in the respective “product” (proteins, enzymes etc.) can be modulated by external factors. For instance modifications of the biochemical state of the genes like methylation or acetylation regulate gene expression. Resulting from this modulation of the gene expression the respective pathways in the cell are activated or not.
It is known that a prior injury to the peripheral axons of sensory neurons activates the neuronal pro-regenerative program. Dr. Giovanni’s team found that acetylation on regeneration-associated genes is required for neurite outgrowth. The hypothesis is that signals coming from a periphery injury (retrograde signaling) are responsible for the acetylation and for the switch to a pro-regenerative state of the gene expression. Preliminary data show that this “pro-regenerative” acetylation is mediated by the molecule (histone acetyltransferase) PCAF.
The aims of this proposal expand upon these current data and are:
- Elucidate the retrograde injury signals responsible for the acetylation on regeneration-associated genes
- Investigate the ability of PCAF to enhance axonal regeneration and function of ascending sensory fibers in the injured spinal cord
These experiments will demonstrate whether and how retrograde axonal signals influence
epigenetic modifications and whether they may promote axonal regeneration following spinal injuries. Ultimately, these studies may lead to a pharmacological modification of the epigenome as a novel strategy to enhance axonal regeneration and functional recovery after SCI.