The absence of treatment to overcome CNS regenerative failure is pointing out our lack of knowledge in the detailed mechanisms of neuronal growth, repair and their fine-tuning during development and injury. I will use a combination of in-vivo models of neuronal development, CNS injury (optic nerve and spinal cord), high throughput analysis and biochemistry, to explore fundamental and yet unexplored mechanism during CNS injury. It will open up new ways for innovative therapeutic development for CNS trauma but also to the large spectrum of neurodegenerative diseases.

Unlike embryonic neurons, mature neurons from central nervous system lose the competence to regrow an axonal process after its ablation. It has been now well demonstrated that this poor regenerative ability is due to their intrinsic capability. In order to counteract this phenomenon, we need to understand the molecular changes induced by the injury within the neuron himself. To reach this goal, I develop a project, combining cutting edge mass spectrometry approach, as well as in vivo experiment, to analyze the effect of the optic nerve injury on Retina Ganglia Cells. Our results allowing us to create a “picture” of the neurons after injury and based on this analysis, we identify at least two new interesting targets that can promote neurons survival and axon regeneration.First I identified a new transcription factors that can induce strong regeneration when expressed before and/or after injury. I highlighted that this protein could act as an interesting target for treatment. In addition, from the protein profiling, I uncovered a networks of molecular pathways that in concert to induce axon regeneration but manipulating simultaneously those pathway I achieve a strong axonal regeneration that could reach the brain targets. We also focused our attention on a second target, a microtubule associated protein. Our study revealed that this protein is a critical regulator for one of the major step of axon regeneration, the formation of new growth cone. Altogether, my work gives new insights in the field of axon regeneration, at the level of fundamental processes as well as translational therapeutic perspectives.

Protein synthesis is a fundamental cell process and ribosomes - particularly through the ribosomal RNA that display ribozyme activity - are the main effectors of this process. Ribosome biogenesis is a very complex process involving transcriptional as well as many post-transcriptional steps to produce functional ribosomes. It is now well demonstrated that ribosome production is enhanced in cancer cells and that ribosome biogenesis plays a crucial role in tumor progression. However, at present there is an important lack of data to determine whether the entire process of ribosomebiogenesis and ribosome assembly is modified during tumor progression and what could be the potential impact on the dysregulation of translational control that is observed in cancer cells. My work during my Ph.D was mainly focused on analysis of the structure and function of ribosomes in different model of cancer cells. I particularly worked on rRNA processing (cleavage maturation) and methylation. I develop during my Ph.D a new quantitative method to analyze rRNA 2’-O-methylation, a major rRNA modification. My work was able to highlight a link between tumor progression, rRNA methylation and IRES-dependent translation initiation of oncogene and tumor suppressor.

The ribosome is the central effector of protein synthesis, and its synthesis is intimately coordinated with that of proteins. At present, the most documented way to modulate ribosome biogenesis involves control of rDNA transcription by RNA polymerase I (RNA Pol I). My work show that after infection of human cells with herpes simplex virus type 1 (HSV-1) the rate of ribosome biogenesis is modulated independently of RNA Pol I activity by a dramatic change in the rRNA maturation pathway. This process permits control of the ribosome biogenesis rate, giving the possibility of escaping ribosomal stress and eventually allowing assembly of specialized kinds of ribosomes.