Axon regeneration is a fundamental and conserved property of nervous systems. But although axon regeneration can restore function after nerve injury, regeneration often fails. Thus, a key question in the field is to discover what determines the regenerative capacity of injured neurons. This proposal investigates new mechanisms that function in the injured neuron and that help determine whether or not regeneration occurs. The long-term goal is to gain a comprehensive understanding of the cellular functions that link neuronal injury to successful regeneration. The specific goal of this project is to analyze three novel and interrelated mechanisms that regulate axon regeneration at the genetic, cellular, and molecular level. The project uses a combination of in vivo approaches that culminate in analysis of the injury response in individual neurons. The central hypothesis is that the three novel mechanisms act in a pathway that regulates axon regeneration and the neuronal injury response. However, each Aim is independent and will result in fundamental discoveries about the cell biology of axon regeneration even if the individual mechanisms operate in parallel rather than in a linear pathway.
Each Aim i s supported by extensive preliminary data, as well as by novel biological concepts and experimental approaches. Completion of these Aims will describe fundamental cellular mechanisms that mediate axon regeneration.

Public Health Relevance

The proposed research investigates novel mechanisms that regulate axon regeneration, a critical process that can restore function after nerve injury. Failur of neurons to regenerate after injury results in permanent functional loss and is a significant burden on public health. The research proposed here is expected to result in fundamental knowledge that suggests ways to promote functional recovery after nerve injury.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Synapses, Cytoskeleton and Trafficking Study Section (SYN)
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Jakeman, Lyn B
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Yale University
Schools of Medicine
New Haven
United States
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Kurshan, Peri T; Merrill, Sean A; Dong, Yongming et al. (2018) ?-Neurexin and Frizzled Mediate Parallel Synapse Assembly Pathways Antagonized by Receptor Endocytosis. Neuron 100:150-166.e4
Byrne, Alexandra B; Hammarlund, Marc (2017) Axon regeneration in C. elegans: Worming our way to mechanisms of axon regeneration. Exp Neurol 287:300-309
Han, Sung Min; Baig, Huma S; Hammarlund, Marc (2016) Mitochondria Localize to Injured Axons to Support Regeneration. Neuron 92:1308-1323
Byrne, Alexandra B; McWhirter, Rebecca D; Sekine, Yuichi et al. (2016) Inhibiting poly(ADP-ribosylation) improves axon regeneration. Elife 5:
Wang, Xingxing; Sekine, Yuichi; Byrne, Alexandra B et al. (2016) Inhibition of Poly-ADP-Ribosylation Fails to Increase Axonal Regeneration or Improve Functional Recovery after Adult Mammalian CNS Injury. eNeuro 3: