Medical Student Research Fellowship for Summer 2006
Mentor: Shuxin Li
Room number: ND4.124B
Mail Code: 8813
Phone number: 56231
Project title: Promoting neuronal regeneration and repair in the damaged central nervous system
Human subjects IRB approved project number (where applicable):
Animal subjects IRB approved project number (where applicable): 1040-05-01-1
Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects): both animal-based and basic research
Brief Description of Project:
The long term goal in my laboratory is to elucidate the molecular and cellular mechanisms underlying neuronal damage and growth failure and to develop the successful strategies for recovering neurological deficits induced by axonal damage. The research advance to promote CNS axonal extension may lead to a successful therapy for recovering functional loss due to axon damage. One area of our research is to characterize axonal growth inhibition mediated by such extrinsic factors as myelin-derived molecules. Our recent studies suggest that myelin protein Nogo-A functions as a potent inhibitor for axonal elongation following a CNS axonal injury (Neuron, 2003, 38:187-199) and intervention of Nogo-A via pharmacological or transgenic approaches has enhanced a significant axonal regeneration following spinal cord injury in rodents. Particularly, we developed the selective antagonistic peptide NEP1-40 (Nature, 2002, 417:547-551; J Neurosci, 2003, 23: 4219-422) and ectodomain protein NgR(310)ecto (J Neurosci, 2004, 24:10511-10520, Mol & Cell Neurosci 2005, 29:26-39), which block the binding of potent inhibitory domain Nogo-66 to Nogo-66 receptor protein. Pharmacological or transgenic applications of these reagents to axonal injured rodents have remarkably promoted axonal regeneration and locomotion functional recovery following a spinal cord lesion. Due to the controversy on the role of Nogo from the Nogo-mutant studies, we are further studying the myelin-associated growth inhibition by silencing gene expression of the relating molecules via short RNA interference. This project is aimed to develop a more potent approach to suppress myelin derived inhibitions and to identify the smallest molecules for promoting axonal regeneration in the mammalian CNS. Our recent experiments have indicated the exciting results on CNS axonal repair by targeting myelin-associated inhibitions.
Another emphasis of our studies focuses on the intracellular signaling mechanisms underlying axonal growth failure in the injured CNS. In addition to myelin inhibitor Nogo-A, a number of other proteins are responsible for the axonal growth collapse in the brain and spinal cord. A more successful strategy to promote axonal regeneration and functional recovery should target the multiple inhibitory factors. Because several inhibiting molecules appear to intracellularly converge on one signaling pathway relating to axonal elongation, an alternative approach to overcome various growth inhibitions is to influence the convergent downstream signals. One of our research projects is to characterize the intracellular regulating signals downstream to axonal growth molecules and to identify the more effective methods to block numerous growth inhibitions at intracellular level using transgenic and molecular/cell biological approaches.
The third research interest relating to CNS neuronal repair is to understand the cellular and molecular basis for myelin damage along degenerated axons in the CNS. Myelin sheath is essential for signal conduction along axons and loss of this structure following a CNS injury usually contributes to the functional deficits in many patients. A major research focus in my lab is to elucidate the molecular mechanisms underlying myelination of oligodendrocytes and demyelination after a CNS injury using in vitro and in vivo neurobiological approaches, thus promoting the re-myelination of CNS axons. Our understanding of molecular regulation of myelinating glial death will provide novel intervention target for functionally repairing injured CNS axons.
Previous Research Activities or Publications with Medical Students:
" Li S, Liu BP, Budel S, Li M, Ji B, Walus L, Jirik A, Rabacchi S, Choi
E, Worley D, Sah DWY, Pepinsky B, Lee D, Relton J and Strittmatter SM. Blockade
of Nogo-66, MAG plus OMgp by soluble Nogo-66 receptor promotes axonal sprouting
and recovery after spinal injury. J Neurosci, 24: 10511-10520, 2004. (Highlighted
" Li S, Kim JK, Budel S, Hampton TG and Strittmatter SM. Transgenic inhibition of Nogo-66 receptor function allows axonal sprouting and improved locomotion after spinal injury. Mol Cell Neurosci, 2004, in press.
" Kim JK*, Li S*, GrandPre T, Qiu K, Greer CA and Strittmatter SM. Axon Regeneration in young adult mice lacking Nogo-A/B. Neuron, 2003; 38: 187-199. 2003. (*Co-first author).
" Li S and Strittmatter SM. Delayed systemic Nogo-66 receptor antagonist after spinal cord injury promotes recovery. J Neurosci, 2003; 23: 4219-4227. (Highlighted paper).
" Zheng B, .Ho C, .Li S, Keirstead H, Steward O, Tessier-Lavigne M. Lack of enhanced spinal regeneration in Nogo deficient mice. Neuron 2003; 38: 213-224.
" GrandPré T*, Li S * and Strittmatter SM. Nogo-66 receptor antagonist peptide promotes axonal regeneration. Nature, 2002; 417: 547-551. (*Co-first author).
" Li S and Stys PK. Mechanisms of ionotropic glutamate receptor-mediated excitotoxicity in isolated spinal cord white matter. J Neurosci 2000; 20: 1190-1198. (Cover Figure)
" Li S, Mealing GAR, Morley P, Stys PK. Novel injury mechanism in anoxia and trauma of spinal cord white matter: glutamate release via reverse Na+-dependent glutamate transport. J Neurosci 1999; 19: RC 16(1-9). (Cover Figure)
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