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）导致从分子到器官水平的无与伦比的结构损伤; 随后出现广泛的功能障碍，包括适应不良的激活和/或内源性损伤的失调- 反应机制。我们的长期目标是表征调节细胞凋亡的分子机制。 TBI后进行性脑神经变性和相关的神经损伤。退伍军人是一个独特的 一组脑外伤患者，因为军事TBI的特点，特定的条件下，前后创伤， 影响神经病理学的发展最近的研究表明，压力会导致显著和广泛的- 可能由促炎性全身和中枢（大脑）介导的对大脑的各种负面影响 机制等这些过程可能是创伤后应激障碍（PTSD）发展的基础。 与TBI的关系变得更加重要。我们假设，暴露于TBI前后 应激改变了TBI中神经炎症和神经变性进展的轨迹;加速和 延长神经病理过程，最终导致自我维持和复杂的TBI-PTSD 条件小胶质细胞从神经恢复表型到功能障碍表型的适应不良转化 脑创伤后的神经毒性激活导致进行性神经变性和认知能力下降。 一个关键的未解决的问题是TBI后小胶质细胞的转化机制以及应激的影响 这些机制？微小RNA是小的非编码RNA，在基因表达后负调节基因表达 转录水平。由于microRNA可以靶向多个基因，因此它们可以同时调节整个通路， 或在神经炎症和迟发性神经元细胞死亡中起作用的相关通路的集合。因此，我们认为， microRNA是进化设计来同时调节多个分子通路的;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，在细胞内[特异性] microRNAs通路[包括miR-223和miR-155]发生了变化， 表型不平衡有利于促炎和神经毒性小胶质细胞激活状态， 炎症消退小胶质细胞表型，促进TBI后的恢复和修复。我们假设 双重应激-TBI暴露诱导小胶质细胞转化为明显的促炎性和神经毒性， 表型，导致进行性神经变性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 通过解决以下具体目标， 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]并增强TBI后的神经变性。 目的2：在TBI前应激暴露后[抑制促进神经炎症的miR-223和miR-155]， 减轻创伤依赖性神经炎症和神经变性并改善神经功能。 目的3：TBI+应激后[抑制促进神经炎症的miR-223和miR-155]将促进神经炎症的发生。 神经修复性小胶质细胞表型和减弱慢性神经炎症，以及减少 神经变性并导致神经功能的持续改善。