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

创伤性脑损伤(TBI)导致从分子到器官层面的无与伦比的结构损害； 随之而来的是广泛的功能障碍，包括适应不良激活和/或内源性损伤调节失调- 应对机制。我们的长期目标是确定调节 脑外伤后进行性脑神经变性和相关的神经损害。退伍军人是一个与众不同的人 本组脑外伤患者因军事颅脑损伤的特点，伤前伤后情况特殊 影响发展中的神经病理学。最近的研究表明，压力会导致显著和广泛的- 对大脑的一系列负面影响，可能是由促炎的全身和中枢(大脑)介导的 机械装置。这些过程可能支持创伤后应激障碍(PTSD)的发展 在与脑外伤相关的情况下变得更加重要。我们假设脑损伤前和/或脑损伤后暴露于 应激改变了脑外伤后神经炎症和神经退行性变的发展轨迹；加速和 延长神经病理过程，最终导致自我维持和复杂的创伤性创伤后应激障碍 条件。小胶质细胞从神经修复表型到功能障碍的适应不良转变 脑创伤后的神经毒性激活，导致进行性神经变性和认知功能下降。 一个关键的悬而未决的问题是，脑外伤后小胶质细胞的转化机制是什么？应激的影响是什么？ 在这些机制上？MicroRNAs是一种非编码的小RNA，它在转录后负性调节基因的表达。 转录水平。由于microRNAs可以靶向多个基因，它们可以同时调节整个途径 或一系列在神经炎症和延迟性神经细胞死亡中起作用的相关通路。因此， MicroRNA是进化设计的，旨在同时调节多个分子途径；因此，是一种 有效操纵细胞反应的理想治疗靶点。 我们的初步数据表明[特定的]microRNAs通路[包括miR-223和miR-155]在 表型失衡有利于促炎和神经毒性小胶质细胞的激活状态 促进脑外伤后恢复和修复的消炎小胶质细胞表型。我们假设 双重应激-脑创伤暴露诱导小胶质细胞向明显的促炎和神经毒性转化 表型，导致进行性神经变性和长期的神经功能障碍；这些过程 包括小胶质细胞和神经元中microRNAs变化的特定程序。我们将对这些小说进行测试 通过解决以下具体目标提出假设： 目的1：应激暴露促进小胶质细胞向促炎和神经毒性表型转变 [与miR-223和miR-155上调相关]，并促进脑损伤后的神经变性。 目的2：[抑制促进神经炎症的miR-223和miR-155]在脑创伤前应激暴露后将 减轻创伤依赖的神经炎症和神经退行性变，改善神经功能。 目的3：[抑制促神经炎症的miR-223和miR-155] 神经恢复性小胶质细胞表型和减轻慢性神经炎，以及减少 神经退化，并导致神经功能的持续改善。

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.