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

MicroRNA 调节途径控制 TBI 后的慢性进行性神经炎症和神经变性

• 批准号: 10359073
• 负责人: BOGDAN ADRIAN STOICA
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10359073
• 关键词: Address; Affective; Attenuated; Brain; Brain Injuries; Cells; Chronic; Clinical Data; Cognitive; Complex; Data; Development; Disease; Exposure to; Flow Cytometry; Functional disorder; Gene Expression; Genes; Genetic Transcription; Goals; Immune; Impaired cognition; Impairment; Inflammation; Inflammatory; Injury; Lead; Mediating; MicroRNAs; Microglia; Military Personnel; Modeling; Molecular; Motor; Nerve Degeneration; Nervous System Physiology; Neurologic; Neurologic Deficit; Neurologic Dysfunctions; Neurons; Organ; Pathway interactions; Patients; Phenotype; Play; Population; Post-Traumatic Stress Disorders; Process; Role; Stress; System; Testing; Therapeutic Intervention; Time; Tissues; Trauma; Trauma patient; Traumatic Brain Injury; United States Department of Veterans Affairs; Untranslated RNA; Up-Regulation; Veterans; cell type; design; improved; nano-string; neurobehavioral; neuroinflammation; neuron loss; neuropathology; neurorestoration; neurotoxic; neurotoxicity; novel; pre-clinical; programs; progressive neurodegeneration; repaired; response; response to injury; restoration; therapeutic target; therapeutically effective; traumatic stress

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.

创伤性脑损伤（TBI）导致无与伦比的结构损伤，从分子到器官水平；和 其次是广泛的功能障碍，包括适应不良激活和/或内源性损伤失调 - 响应机制。我们的长期目标是表征调节的分子机制 TBI后进行性脑神经退行性变化和相关的神经系统障碍。退伍军人是一个独特的 一组脑外伤患者，因为军事TBI在创伤之前和之后具有特定条件 影响正在发展的神经病理学。最近的研究表明，压力会导致重要和广泛的 对大脑的负面影响可能是由促炎性系统和中央（大脑）介导的 机制。这些可能支持创伤后应激障碍（PTSD）发展的过程 与TBI结合起来变得更加重要。我们假设暴露于TBI前和/或TBI 压力改变了TBI中神经炎症和神经退行性发展的轨迹；加速和 扩展神经病理学过程，并最终导致自我维持和复杂的TBI-PTSD 健康）状况。小胶质细胞从神经疏松表型转变为功能失调 脑创伤后的神经毒性激活有助于进行性神经退行性和认知能力下降。 一个关键的未解决的问题是哪些机制转化了TBI之后的小胶质细胞，应力的影响是什么 关于这些机制？ microRNA是小的非编码RNA，在后后调节基因表达 转录级别。由于microRNA可以靶向多个基因，因此它们可以同时调节整个途径 或在神经炎症和延迟神经元细胞死亡中发挥作用的相关途径。所以， microRNA是旨在同时调节多个分子途径的进化。因此，是 有效操纵细胞反应的理想治疗靶标。 我们的初步数据暗示[特定] microRNA途径[包括miR-223和miR-155]的变化 表型失衡有利于促炎性和神经毒性的小胶质细胞激活状态 TBI后促进恢复和修复的炎症的小胶质细胞表型。我们假设 双重应力-TBI暴露会导致小胶质细胞转化向独特的促炎和神经毒性转化 表型，导致进行性神经退行性变化和长期神经功能障碍；这些过程 包括小胶质细胞和神经元中microRNA变化的特定程序。我们将测试这些小说 通过解决以下特定目的来假设： AIM 1：促进小胶质细胞向促炎和神经毒性表型的转变 [与miR-223和miR-155上调有关]，并在TBI后增强神经退行性。 目标2：[抑制神经炎症促进miR-223和miR-155] 减弱依赖创伤的神经炎症和神经变性并改善神经功能。 目标3：[抑制神经炎症促进miR-223和miR-155] TBI+应力将促进 神经训练的小胶质细胞表型和衰减慢性神经炎症，并减少 神经变性并导致神经功能的持续改善。