Valeria Cavalli Research Abstract
Permanent disabilities following central nervous system (CNS) injuries result from the failure of injured axons to regenerate and re-build functional connections. The poor intrinsic regenerative capacity of mature CNS neurons is a major contributor to the regeneration failure and remains a major problem in neurobiology. In contrast to CNS neurons, peripheral sensory neurons successfully regenerate injured axons. Our goal is to reveal the principles and mechanisms by which injured sensory neurons re-activate a pro-regenerative program following axon injury and identify potential targets for future treatment of CNS injuries.
1. Retrograde injury signaling. We have focused on the issue of retrograde injury signaling, or how information about an injury is conveyed from the distantly located lesion site in the axon back to the cell body. We have discovered aspects of this mechanism that include the retrograde transport of organelles bearing the adaptor protein JIP3 on their surface and the role of the DLK/JNK signaling pathway in injury signaling and axon regeneration. We also recently explored the mechanisms initiating this retrograde transport and discovered that increased levels of tyrosinated -tubulin at the injury site facilitates retrograde injury signaling and is required to activate a pro-regenerative program. We have also revealed that axon injury elicits a back-propagating calcium wave invading the soma and causing changes in the epigenetic landscape. We are following these studies to uncover the detailed mechanisms controlling axon to soma communication following neuronal injury.
2. Epigenetic and translational regulation of axon regeneration. We are studying the mechanisms by which a pro-regenerative state is reprogrammed following axon injury. Recently, we demonstrated that axon injury elicits an epigenetic switch controlling regenerative competence in sensory neurons. Our studies revealed that axon injury elicits the nuclear export of the histone deacetylases HDAC5, leading to enhanced histone acetylation and activation of a pro-regenerative transcriptional program. Moreover, this study reveals critical differences in epigenetic responses of peripheral and central neurons, and may be transformative in our understanding and approaches to treatment of nerve injuries. Given that epigenetic regulations affects globally, yet specifically, an ensemble of genes, they represents ideal strategies to promote neural repair. We are pursuing our studies to uncover the epigenetic, transcriptional and translational pathways that are induced by axon injury and culminate in the activation of a pro-regenerative program.
3. Microtubule modifications and molecular motors in axon growth and regeneration. Our research also focuses on the microtubule tracks on which injury signals are transported along axons and the role of microtubule post-translational modifications in injured axons. These studies led us to discover that injury to peripheral, but not central neurons induces microtubule post-translational modifications. These modifications are critical for growth cone dynamics and axon regeneration. These findings point to the important roles of microtubule post-translational modifications in the ability of injured axons to regenerate. We have are also studying the role of molecular motors in injury signaling and anterograde transport, particularly the mechanisms that regulate and coordinate molecular motor activity and directionality. We have shown that the motor adaptor JIP3, which is essential for retrograde injury signaling, also functions as a positive regulator of kinesin-1 motility, controlling axon growth in developing neurons as well as axon regeneration.