Intrinsic and extrinsic regulation of injury-induced axonal growth in the CNS: a combinatorial approach with known pathways and exploring the unknown role of microRNAs

• Applicant: Dr. Oliver Tress
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2013 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 235777469

Axon growth and regeneration are of key importance for functional recovery after spinal cord injury. Several mechanisms and molecular pathways that regulate axon growth and regeneration in the adult mammalian central nervous system (CNS) have been identified. PTEN (phosphatase and tensin homolog) negatively regulates the neuron-intrinsic growth capacity while the myelin derived axon growth inhibitors modulate the sprouting of spared axons. Furthermore, chondroitin sulfate proteoglycans (CSPGs) inhibit axon growth after spinal cord injury. Despite the advancement in our understanding of axon growth regulation, there is no cure or effective treatment to promote axon growth and functional recovery to date. Further understanding the interaction between the existing molecular targets and identifying novel molecular targets will allow for the development of effective therapeutic strategies. In the first project I will investigate the functional interplay between extrinsic factor-mediated inhibition and neuron-intrinsic regulation of axon growth after CNS injury. I will combine gene deletion of NgR1 (or Rtn4r; reticulon 4 receptor) and NgR3 (or Rtn4rl1; reticulon 4 receptor-like 1) (receptors for CSPGs and myelin derived axon growth inhibitors) with conditional PTEN deletion in order to assess the consequence on axon sprouting and regeneration in mouse models of CNS injuries. In a second project I aim to identify microRNAs (miRNAs) that regulate injury-induced axonal growth. MiRNAs are small non-coding RNAs of about 22 nucleotides length which post-transcriptionally regulate protein synthesis via interaction with target gene mRNA. I will start by assessing candidate miRNAs that target PTEN and other neuronally expressed regulators of axon growth. In vitro neurite outgrowth and axon regeneration assays and subsequently in vivo CNS injury models will be applied to investigate axon growth after manipulation of miRNA expression. While the first project will allow me to learn the field and contribute to building on existing knowledge in the field of CNS injury and repair, the second project will allow me to explore the unknown role of miRNAs in axon growth and spinal cord repair.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Binhai Zheng, Ph.D.