My laboratory’s research is centered on understanding how peripheral neurons orchestrate their intracellular injury signaling pathways leading to successful regeneration in the mouse model system.
While most tissues in the human body, including peripheral nerves, have a remarkable ability to repair themselves after injury, the central nervous system (CNS) simply does not spontaneously regenerate. The lack of robust axonal regeneration represents one of the major barriers to recovery following CNS trauma, including stroke and spinal cord injury. Recent evidence also implicates axonal dysfunction as an early contributor in many neurodegenerative diseases. Failure to repair CNS axons has remained a recalcitrant problem despite a century of research on the reaction of axons to injury. Understanding injury signaling mechanisms leading to successful regeneration in peripheral neurons will help develop strategies to enhance CNS regeneration following injury. Currently, three major areas of research are under investigation.
First, we are focusing on understanding how information from the site of injury in the axon is communicated to the cell body. The cell body of injured neurons must receive accurate and timely information on the site and extent of axonal damage in order to orchestrate an appropriate response leading to successful regeneration. Our studies have provided important evidence implicating vesicular axonal transport in injury-signaling pathways. We found evidence suggesting that the vesicle associated protein “Sunday Driver” (syd), in collaboration with the stress-activated protein kinase JNK and the molecular motor system transmits damage information along the length of the axon back to the cell body. We have recently characterized the molecular composition of syd-associated vesicles and are currently investigating their function in axonal regeneration, using a combination of biochemical, cell biological and genetic approaches. We are using cultured primary neurons and in vivo injury model to dissect the mechanisms that coordinate molecular motor recruitment and activity, and hence determine transport directionality.
Second, we aim to determine whether the spatio-temporal properties of syd-associated vesicles differ between PNS and CNS neurons in response to axonal injury. The poor regenerative capacity of CNS neurons may in part result from an impaired ability to initiate retrograde axonal transport of signals following injury. While our biochemical results implicate retrograde transport of syd-associated vesicles in injury signaling, the precise dynamic properties of these vesicles in the PNS and CNS neurons are not known. We combine in vitro and intra-vital fluorescent imaging approaches with axonal injury models to directly assess the dynamic properties of syd-associated vesicles in response to injury.
Third, we are elucidating the mechanisms regulating vesicular transport in relation to neuronal development, survival and function. The extension, branching, and connection of axons play a central role during development of the nervous system. Relatively little is known about the nature and the role of the vesicles transported along axons and the machinery regulating their transport. We have recently shown that in the CNS, syd vesicles are found at the synaptic terminal but are morphologically and functionally distinct from synaptic vesicles. We employ an array of biochemical, cell biological and genetic approaches to characterize the role of known and novel proteins associated with syd-vesicles in CNS disease models, including epilepsy, autism and schizophrenia.
The long-term goals of our research are 1) to provide a deeper understanding of the molecular determinants leading to successful axonal regeneration and 2) to reveal the role of vesicular transport in neuronal development and function.
Research Photos (Click to Enlarge)
Research Publications
Abe N, Cavalli V (2008 Aug 7). Nerve injury signaling. Curr Opin Neurobiol. Full Article >
Cavalli, V. 2008. Transport dependent - damage signaling. In: Encyclopedia of Neuroscience, L.R. Squire, Editor-in-Chief., Academic Press, Oxford
Haghnia M, Cavalli V, Shah SB, Schimmelpfeng K, Brusch R, Yang G, Herrera C, Pilling A, Goldstein LS (2007 Jun). Dynactin is required for coordinated bidirectional motility, but not for dynein membrane attachment. Mol Biol Cell. 18 (6): 2081-9. Full Article >
Cavalli V, Kujala P, Klumperman J, Goldstein LS (2005). Sunday Driver links axonal transport to damage signaling. J Cell Biol. 168: 775-87. Full Article >
Cavalli V, Corti M, Gruenberg J (2001). Endocytosis and signaling cascades: a close encounter. FEBS Lett. 498: 190-6. Full Article >
Cavalli V, Vilbois F, Corti M, Marcote MJ, Tamura K, Karin M, Arkinstall S, Gruenberg J (2001). The stress-induced MAP kinase p38 regulates endocytic trafficking via the GDI:Rab5 complex. Mol Cell. 7: 421-32. Full Article >
Contact Info
Valeria Cavalli, Ph.D
Office Location: 459 McDonnell
Office Phone: 314-362-3540
Campus Box: 8108
Fax: 314-362-3446
cavalli@pcg.wustl.edu
