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Cell Cycle Regulation & Secondary Injury

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Traumatic brain injury (TBI) induces secondary injury mechanisms, including cell cycle activation (CCA), that not only can lead to direct neuronal cell death but also to microglia and astrocyte activation followed by secondary neurotoxicity and ultimately to neurological dysfunction. As clinical trials of neuroprotective drugs to treat traumatic brain injury (TBI) have failed to date, there is a critical need to identify new therapeutic strategies for this common and devastating disorder. Using multiple models of experimental brain trauma, we have shown that CCA represents a therapeutically relevant mechanism responsible for neuronal cell death and microglial activation/secondary neurotoxicity. Historically, post-mitotic cells such as neurons were thought to have permanently entered G0 phase and were incapable of entering the cell cycle. However, recent studies indicate that cell cycle re-entry of mature differentiated post-mitotic neurons occurs, but once activated it results in apoptosis rather than neuronal proliferation. We have demonstrated that cell cycle inhibition via pharmacological intervention with cyclin-dependent kinase (CDK) inhibitors or genetic ablation of cell cycle regulators improves neurobehavioral function, and attenuates TBI-induced progressive neurodegeneration and neuroinflammation across multiple injury models and species. Our current ongoing work focuses on using transgenic models and a drug-based approach to demonstrate key role of specific inducers of CCA after TBI, such as E2F 1, 2 and 3. In addition to investigating acute injury mechanisms, we are also expanding the scope of our research to TBI-induced chronic neurodegeneration in order to evaluate our hypothesis that chronic CCA after TBI is an important contributing factor to trauma-induced delayed neurodegeneration.