| Spinal cord injury (SCI) is often physically, financially, and emotionally devastating. The failure of axons to regenerate following trauma to the central nervous system (CNS) is well known, and remains one critical focus of SCI research. In addition, the inflammatory response to SCI has received attention for its role in a number of detrimental and beneficial processes after injury. Inflammatory complement proteins are increased in the spinal cord after SCI, but the functions these proteins exert in such an injured CNS environment are poorly understood. The central hypothesis for the presented dissertation projects was that complement proteins affect neurite outgrowth and axon regeneration. Using morphological assays for neurite outgrowth in primary neuron cultures as described in detail in chapter 2, data in support of this hypothesis for both C1q and C3 was generated, and is shown in chapters 3 and 4, respectively.;Complement C3 exacerbated myelin mediated neurite outgrowth inhibition, potentially through a mechanism involving myelin cleavage of C3 and subsequent C3b induced reduction in outgrowth with correlated cellular toxicity. When tested in an animal model of SCI, C3 deficient mice responded as predicted based on the culture data, with increased regeneration of conditioned sensory axons. These results are detailed in chapter 3.;In chapter 4, evidence is presented for C1q mediated increase of neurite outgrowth on inhibitory myelin, and more specifically C1q on myelin associated glycoprotein (MAG) substrate in comparison to inhibitor alone. Complement C1q also abolished MAG mediated axon turning in culture, and while C1q deficiency did not affect regenerated axon length, it did increase axon turning in the spinal cord following injury with conditioning lesion. C1q did not appear to play a necessary role in corticospinal axon sprouting or midline crossing after dorsal hemisection, however, as shown in chapter 5. |
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