Although neurons in the peripheral nervous system can spontaneously regenerate injured axons, those in the central nervous system have to be coaxed to regenerate. Both extrinsic inhibitor factors and intrinsically lower growth capacity limi central regeneration. Conditioning neurons by peripheral nerve injury can increase the intrinsic growth capacity of neurons. This increase in intrinsic growth capacity is accompanied by an increase in localized protein synthesis directly within regenerating axons. We have recently shown that intra-axonal translation of ?-actin, GAP-43, and Importin ?1 mRNAs is needed for peripheral nerve regeneration (Donnelly et al., 2011;Perry et al., 2012). Limiting of the delivery of these mRNAs into peripheral axons compromises regeneration. Moreover, increasing delivery of ?-actin and GAP-43 mRNAs into axons increases axonal growth, including axonal growth in the developing spinal cord (Donnelly et al., 2013). Although the extent to which mRNAs can localize into CNS axons after spinal cord injury has not been thoroughly tested, ?-actin's 3'UTR can drive mRNA into central process of sensory neurons after spinal cord injury (Willis et al., 2011). This suggests that local mRNA translation occurs in injured axons in the spinal cord. Over the past funding period, we have defined RNA localization elements for multiple axonal mRNAs encoding regeneration-associated genes like ?-actin. These provide a singularly unique resource of cellular tools to move our studies from in vitro preparations to in vivo neural injury models. The experiments proposed here will take advantage of these tools to determine if modifying the axonal transcriptome can be used to increase the intrinsic growth capacity of adult neurons in peripheral and central nervous systems. The studies in Aims 1 and 2 will tell us if transport into PNS and CNS axons is regulated by injury, the extent to which this compares to PNS axons, and whether axonal protein synthesis can be used to facilitate axonal regeneration in both the PNS and CNS in vivo. The studies in Aim 3 examine whether and how CNS growth promoting and growth inhibiting agents modulate translation in axons uncovering novel genetic and/or pharmacological approaches to alter the axon's translational response to stimuli that impede regeneration.
Injury of peripheral nerve, brain, and spinal cord can result in permanent disability if the neuronal processes traversing the injured regions cannot regenerate. Despite advances in understanding the mechanism of failed regeneration, there are still no successful treatments for increasing regeneration. This project focuses on recently recognized growth mechanisms intrinsic to neuronal processes that we believe can be used to both increase regeneration.
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|Kalinski, Ashley L; Sachdeva, Rahul; Gomes, Cynthia et al. (2015) mRNAs and Protein Synthetic Machinery Localize into Regenerating Spinal Cord Axons When They Are Provided a Substrate That Supports Growth. J Neurosci 35:10357-70|
|Gardiner, Amy S; Twiss, Jeffery L; Perrone-Bizzozero, Nora I (2015) Competing Interactions of RNA-Binding Proteins, MicroRNAs, and Their Targets Control Neuronal Development and Function. Biomolecules 5:2903-18|
|Merianda, Tanuja T; Coleman, Jennifer; Kim, Hak Hee et al. (2015) Axonal amphoterin mRNA is regulated by translational control and enhances axon outgrowth. J Neurosci 35:5693-706|
|Gomes, Cynthia; Merianda, Tanuja T; Lee, Seung Joon et al. (2014) Molecular determinants of the axonal mRNA transcriptome. Dev Neurobiol 74:218-32|
|Donnelly, Christopher J; Park, Michael; Spillane, Mirela et al. (2013) Axonally synthesized Î²-actin and GAP-43 proteins support distinct modes of axonal growth. J Neurosci 33:3311-22|
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