TNFR2 Activation Improves Functional Recovery Following SCI and Induces Neurite Outgrowth in-vitro

About 12,000 people every year are diagnosed with spinal cord injuries (SCI), the majority of which go through traumatic life changes associated with some degree of paralysis. With an extremely high cost of living and a long list of side effects, SCI remain one of the most challenging models to solve. Therapies for SCI have been developed and while some improvement has been witnessed, we are a long way from establishing a therapy that leads to total recovery from SCI. Due to the nature of the CNS, injuries to the spine create many challenges for researches due to the increase in inflammatory, and inhibitory molecules that lead to increased cell death and the inability to regrow axons. Therapies have attempted to address the inflammation elicited by SCI or the inhibitory microenvironment created because of the injury using various drugs that inhibit molecules such as Tumor Necrosis Factor (TNF). While molecules like TNF mediate much of the detrimental effects after SCI, TNF is a complex molecule with two receptors (TNFR1 and TNFR2) that activate very different pathways. In our study we deliver an agonist for the TNF receptor II, which unlike TNF receptor I has proven to be neuroprotective in various disease models, as method for SCI therapy. We found that TNFR2 activation after SCI lead to a significant improvement in functional recovery in mice, which we determined was the result of neural circuitry reorganization. Furthermore, we found that TNFR2 activation lead to an increase in neurite outgrowth in Rat cortical neurons in-vitro. We determined that TNFR2-mediated neurite outgrowth was the result of BDNF secretion after TNFR2 activation, and the subsequent activation of pathways that ultimately effected the actin dynamics after. We also determined that TNFR2-mediated neurite outgrowth was assisted by a separate pathway that was mediated by JNK activation and a downstream stathmin protein that is known to effect microtubule dynamics. We believe that these TNFR2-mediated effects that have been characterized in vitro may play a significant role in results we see after TNFR2 treatment in SCI mice and may eventually lead to the creation of a new SCI therapy.Ph.D., Biological Sciences -- Drexel University, 201