One of the major obstacles to axonal regeneration in the adult CNS is inhibitors associated with myelin, such as MAG. However, axonal growth can be encouraged in an inhibitory environment both in culture and in vivo if the neuronal cAMP levels are elevated, either with analogues such as db cAMP or by priming neurons with neurotrophins. One situation where spontaneous CNS axon regeneration does occur is of dorsal root ganglion axons if the peripheral branch of the same neuron, the dorsal root ganglion (DRG) neuron, is lesioned one week before - the conditioning lesion (CL) effect, which is cAMP dependent. Both the cAMP and the CL effects are dependent on transcription and one gen that is up-regulated is for the enzyme Arginase I (Arg I), which is key in the synthesis of polyamines. The polyamine, spermidine, can overcome inhibition by MAG in culture and promotes optic nerve regeneration in vivo. Furthermore, spermidine promotes regeneration by activating the kinase CDK5 by hypusinating the eukaryotic initiation factor 5A (eIF5A), resulting in an increase in translation of the CDK5 activator p35.
In Aim 1 a the CDK5 substrates that are activated in response to polyamine will be identified and characterized for their role in overcoming inhibition and promoting regeneration in vivo.
Aim 1 b will address the cross-talk between the neurotrophin and MAG signaling pathway, focusing on the ability of MAG to block the activation of the small GTPase, Rap1, by neurotrophin. Strong preliminary data suggest that both the cAMP and CL effects require local translation in the axon to promote regeneration in an inhibitory environment.
In Aim 2 mRNA and microRNAs that increase in the processes after both a CL and treatment with db cAMP will be identified.
In Aim 3 those mRNAs and microRNAs that increase after both conditions will be characterized (over-expression, knock-down) for a possible role in promoting regeneration in the presence of MAG in culture and in promoting regeneration in vivo. Through the experiments described in this proposal not only will our understanding be advanced of the mechanism of action of agents known to promote regeneration in vivo but novel agents will be identified. This in turn will reveal novel targets for intervention and drug development to promote axonal regeneration in vivo.

Public Health Relevance

The identification of novels agents/mechanisms that promote axonal regeneration will reveal novel targets for therapeutic intervention and drug development to promote axonal regeneration in humans.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Owens, David F
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Hunter College
Schools of Arts and Sciences
New York
United States
Zip Code
He, Huifang; Deng, Kangwen; Siddiq, Mustafa M et al. (2016) Cyclic AMP and Polyamines Overcome Inhibition by Myelin-Associated Glycoprotein through eIF5A-Mediated Increases in p35 Expression and Activation of Cdk5. J Neurosci 36:3079-91
Siddiq, Mustafa M; Hannila, Sari S; Carmel, Jason B et al. (2015) Metallothionein-I/II Promotes Axonal Regeneration in the Central Nervous System. J Biol Chem 290:16343-56
Hannila, Sari S; Siddiq, Mustafa M; Carmel, Jason B et al. (2013) Secretory leukocyte protease inhibitor reverses inhibition by CNS myelin, promotes regeneration in the optic nerve, and suppresses expression of the transforming growth factor-? signaling protein Smad2. J Neurosci 33:5138-51
Perdigoto, Ana Luisa; Chaudhry, Nagarathnamma; Barnes, Gregory N et al. (2011) A novel role for PTEN in the inhibition of neurite outgrowth by myelin-associated glycoprotein in cortical neurons. Mol Cell Neurosci 46:235-44
Deng, Kangwen; He, Huifang; Qiu, Jin et al. (2009) Increased synthesis of spermidine as a result of upregulation of arginase I promotes axonal regeneration in culture and in vivo. J Neurosci 29:9545-52
Siddiq, Ambreena; Aminova, Leila R; Troy, Carol M et al. (2009) Selective inhibition of hypoxia-inducible factor (HIF) prolyl-hydroxylase 1 mediates neuroprotection against normoxic oxidative death via HIF- and CREB-independent pathways. J Neurosci 29:8828-38
Aminova, Leila R; Siddiq, Ambreena; Ratan, Rajiv R (2008) Antioxidants, HIF prolyl hydroxylase inhibitors or short interfering RNAs to BNIP3 or PUMA, can prevent prodeath effects of the transcriptional activator, HIF-1alpha, in a mouse hippocampal neuronal line. Antioxid Redox Signal 10:1989-98
Hannila, Sari S; Filbin, Marie T (2008) The role of cyclic AMP signaling in promoting axonal regeneration after spinal cord injury. Exp Neurol 209:321-32