MicroRNA-regulated Pathways Control Chronic-Progressive Neuroinflammation and Neurodegeneration Following TBI

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Traumatic brain injury (TBI) results in unparalleled structural damage ranging from molecular to organ levels; and followed by widespread dysfunctions including maladaptive activation and/or dysregulation of endogenous injury- response mechanisms. Our long-term goal is to characterize the molecular mechanisms that modulate progressive brain neurodegeneration and associated neurological impairments after TBI. Veterans are a distinct group of brain trauma patients because military TBI features specific conditions, before and after trauma that impact the developing neuropathology. Recent studies have shown that stress results in significant and wide- ranging negative effects on the brain that may be mediated by pro-inflammatory systemic and central (brain) mechanisms. These processes that may underpin the development of post-traumatic stress disorder (PTSD) become even more significant in association with TBI. We hypothesize that exposure to pre- and/or post-TBI stress changes the trajectory of neuroinflammation and neurodegeneration progression in TBI; accelerating and extending the neuropathological processes and ultimately leading to a self-sustaining and complex TBI-PTSD condition. The maladaptive transformation of microglia from a neurorestorative phenotype to a dysfunctional neurotoxic activation after brain trauma, contributes to progressive neurodegeneration and cognitive decline. A critical unsolved question is what mechanisms transform microglia after TBI and what are the effects of stress on these mechanisms? microRNAs are small noncoding RNAs that negatively regulate gene expression at post- transcriptional level. As microRNAs can target multiple genes, they can concurrently modulate entire pathways or sets of related pathways that play a role in neuroinflammation and delayed neuronal cell death. Therefore, microRNAs are evolutionary designed to concurrently regulate multiple molecular pathways; and thus, are an ideal therapeutic target for effective manipulation of cellular responses. Our preliminary data implicate changes in [specific] microRNAs pathways [including miR-223 and miR-155] in the phenotypic imbalance favoring a pro- inflammatory and neurotoxic microglial activation state over the inflammation-resolving microglial phenotype that promotes restoration and repair following TBI. We hypothesize that dual Stress-TBI exposure induces microglia transformation toward a distinct pro-inflammatory and neurotoxic phenotype, causing progressive neurodegeneration and long-term neurological dysfunctions; these processes include a specific program of microRNAs changes in microglia and neurons. We will test these novel hypotheses by addressing the following specific aims: Aim 1: Stress-exposure promotes a shift in microglia toward a pro-inflammatory and neurotoxic phenotype [associated with miR-223 and miR-155 upregulation] and enhances neurodegeneration after TBI. Aim 2: [Inhibition of neuroinflammation-promoting miR-223 and miR-155] following pre-TBI stress exposure will attenuate trauma-dependent neuroinflammation and neurodegeneration and improve neurological function. Aim 3: [Inhibition of neuroinflammation-promoting miR-223 and miR-155] after TBI+stress will promote the neurorestorative microglial phenotype and attenuate chronic neuroinflammation, as well as reduce neurodegeneration and lead to sustained improvements of neurological function.