Targeting the CBP/p300 acetyltransferase with a small-molecule activator to enhance axon regeneration and functional recovery after spinal cord injury
Funded in: 2017, 2018, 2019
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Problem: lack of regrowth of neuronal fibres in the spinal cord
Target: epigenetical program in regulating gene expression
Goal: pharmacological activation of epigenetical reprogramming on regenerative genes
Millions of people currently live with a spinal cord injury (SCI) which results in permanent deficits in motor, sensory, urinary, sexual and cardiovascular function. SCI's are caused by an injury to neuronal fibres that then fail to regrow in the central nervous system (CNS), one reason for this lack of regrowth is an ineffective neuronal-intrinsic response. Understanding why neurons do not respond to an injury and fail to initiate a robust regrowth response could lead to new therapies to enhance fibre regeneration.
Epigenetics is the study of long-lasting changes in gene expression that are not caused by an alteration to the genetic code itself. One way to epigenetically reprogram neurons is to modify their histone proteins, which play an important role in regulating gene expression. Histone modifications are an attractive target for SCI therapy as they can cause broad changes to biological processes and recent studies have shown that epigenetically reprogramming neurons can enhance their intrinsic regrowth capacity.
Our aim is to investigate the effect of pharmacologically activating a histone modifier called “CBP/p300” on fibre regrowth and recovery of function after SCI. We will use a novel, specific, small-molecule activator of “CBP/p300” that our preliminary results suggest can enhance fibre regrowth. We will then identify the specific molecular mechanism responsible for the enhanced fibre regrowth and functional recovery that occurs in neurons after pharmacologically activating “CBP/p300”.
This could provide important insights in terms of novel regenerative therapeutics for SCI and furthermore could lead to the identification of novel molecular targets to enhance fibre regrowth and recovery after SCI.