Axon Guidance. Matthew Blewitt

Transcription

1 Axon Guidance Matthew Blewitt

2 Overview Axonal development PNS regeneration CNS regeneration Future directions Brain Repair

3 Axonal Development Neurite growth cone

4 Growth Cone Interactions Target Cell Molecular guidance cues Netrin, slit, semaphorins, ephrins Trophic factors Adjacent Cells NCAMs, cadherins Extracellular Matrix Laminin, collagen, fibronectin

5 Synapse Formation Gradual process Receptor rearrangement May use the some of the same adhesion molecules as guidance

6 Peripheral Nerve Damage More than 200,000 procedures/year Limited regeneration Schwann cells provide guidance and support

7 Gap limitations Target acquisition Peripheral Nerve Injury

8 Peripheral Nerve Repair Nerve repair is fairly successful but can have detrimental side effects Most current treatments do not provide complete recovery Gaps over 1cm require bridge Nerve autograft Autoveingraft < 3cm gap images/

9 Spinal Cord Injury 12,000-15,000 traumatic spinal cord injuries/year US\ ~10,000 of which are permantly paralyzed Young healthy individuals age Motor vehicle accidents 44.5% Falls (45 and older) 18.1% Violence 16.6% Sports (diving) 12.7%

10 CNS Injury

11 CNS Injury What is the difference between CNS and PNS injury? Schwann cells versus oligodendrocytes and astrocytes No gene expression Formation of retraction neuroma Growth inhibiting molecules Microglia, macrophage, astrocytes and glial scar

12 Inhibiting Molecules Oligodendrocyte and myelin associated proteins Nogo and myelin associated glycoprotein (MAG) IN-1 antibody successful Proteoglycans found in the glial scar

13 Spinal Cord Treatment Steroids to reduce swelling that may help take stress off of axons Surgery to remove tissue or fluid pressure Bed rest and traction to reset anatomic position Rehabilitation All of these are to alleviate excess stress on axons but do not heal damage

14 Current Research Neural guidance conduits Biological Vein grafting Conduit filled with predegenerated skeletal muscle Decellularized nerve grafts Collagen nerve tubes Synthetic Polymer based Necessary adhesion molecules must be crosslinked

15 CNS Specific Research Antibodies to growth inhibiting factors Electrical stimulation DRGs stimulated but not guided Peripheral nerve and Schwann implantation PNS will not grow into CNS Fetal tissue transplants Olfactory glial cells May work better than Schwann because enter CNS Genetic modification

16 Future Outlook More inhibiting molecules need to be identified to be able to produce more antibodies Combined treatments will probably be necessary Immunosuppressant and biocompatibility assessment

17 A note on Brain Damage Complex issue on its own There is adult neurogenesis in olfactory bulbs and hippocampus Antidepressants have been shown to stimulate neurogenesis

18 References technologies/projects/nerve_regen.html images/ D. Purves, Neuroscience 3 rd Ed. Sinuaer Associated, Inc. Sutherland, Ma. (2004) K. Kalil, G. Szebenyi, E. W. Dent, Journal of Neurobiology 44, 145 (2000). J. Lu, P. Waite, Spine 24, 926 (May 1, 1999). B. J. Dickson, Science 298, 1959 (Dec 6, 2002). B. P. Liu, A. Fournier, T. GrandPre, S. M. Strittmatter, Science 297, 1190 (Aug 16, 2002). D. Hunt, R. S. Coffin, P. N. Anderson, Journal of Neurocytology 31, 93 (Feb, 2002). F. H. Gage, Scientific American 289, 46 (Sep, 2003). L.S. Rummler, R. Gupta, Current Opinion in Orthopaedics 15, 215 (2004)