Therapeutic benefit of targeting neuroinflammation in spinal cord injury with a novel small molecule inhibitor of the RNA regulator HuR

使用 RNA 调节因子 HuR 的新型小分子抑制剂针对脊髓损伤中的神经炎症的治疗益处

• 批准号: 10472150
• 负责人: PETER H KING
• 金额: --
• 依托单位: BIRMINGHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10472150
• 关键词: 3' Untranslated Regions; Acceleration; Acute; Adenine; Affect; Alzheimer' s Disease; Astrocytes; Attenuated; Binding; Biological Assay; Blood Vessels; CCL2 gene; CXCL1 gene; Cells; Central Nervous System; Chest; Cicatrix; Clinical; Contusions; Cytoplasm; Data; Development; Dyes; Early Intervention; Edema; Elements; Event; Extravasation; Financial Hardship; Flow Cytometry; Gelatinase A; Gene Expression Regulation; Health; HuR protein; Immune; Immunohistochemistry; Infiltration; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Interleukin-1 beta; Interleukin-6; Intervention; Invaded; Investigation; Ischemia; Knock-out; Link; Longevity; Measurement; Measures; Mediating; Mediator; Messenger RNA; Microglia; Modeling; Morbidity - disease rate; Motor; Mus; Neuroglia; Neurons; Nitrogen; Nociception; Oligodendroglia; Outcome; Oxygen; Pain; Pathway interactions; Patients; Penetration; Peripheral; Peripheral nerve injury; Persons; Phase; Pilot Projects; Post-Transcriptional Regulation; Production; Proteins; Quality of life; RNA; RNA-Binding Proteins; Recovery; Regenerative capacity; Research Proposals; Rodent Model; Secondary Prevention; Secondary to; Spinal Cord; Spinal cord injury; Stroke; TNF gene; Testing; Therapeutic; Time; Tissues; Toxic effect; Translations; Traumatic Brain Injury; Uridine; Vascular Permeabilities; Veterans; Walking; Water; Work; attenuation; central nervous system injury; chemokine; chronic neurologic disease; chronic neuropathic pain; chronic pain; cytokine; cytotoxic; cytotoxicity; disability; functional improvement; functional outcomes; glial activation; improved; improved outcome; inflammatory milieu; inhibitor; inhibitor therapy; injured; injury recovery; innovation; insight; mRNA Stability; migration; monocyte; motor recovery; nerve injury; neuroinflammation; neuron loss; neuroprotection; neutrophil; new therapeutic target; novel; overexpression; painful neuropathy; posttranscriptional; preclinical study; protein expression; prototype; recruit; response; severe injury; small molecule; small molecule inhibitor; therapeutic target; tissue injury; transgene expression; vasogenic edema; white matter; 3' Untranslated Regions; Acceleration; Acute; Adenine; Affect; Alzheimer' s Disease; Astrocytes; Attenuated; Binding; Biological Assay; Blood Vessels; CCL2 gene; CXCL1 gene; Cells; Central Nervous System; Chest; Cicatrix; Clinical; Contusions; Cytoplasm; Data; Development; Dyes; Early Intervention; Edema; Elements; Event; Extravasation; Financial Hardship; Flow Cytometry; Gelatinase A; Gene Expression Regulation; Health; HuR protein; Immune; Immunohistochemistry; Infiltration; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Interleukin-1 beta; Interleukin-6; Intervention; Invaded; Investigation; Ischemia; Knock-out; Link; Longevity; Measurement; Measures; Mediating; Mediator; Messenger RNA; Microglia; Modeling; Morbidity - disease rate; Motor; Mus; Neuroglia; Neurons; Nitrogen; Nociception; Oligodendroglia; Outcome; Oxygen; Pain; Pathway interactions; Patients; Penetration; Peripheral; Peripheral nerve injury; Persons; Phase; Pilot Projects; Post-Transcriptional Regulation; Production; Proteins; Quality of life; RNA; RNA-Binding Proteins; Recovery; Regenerative capacity; Research Proposals; Rodent Model; Secondary Prevention; Secondary to; Spinal Cord; Spinal cord injury; Stroke; TNF gene; Testing; Therapeutic; Time; Tissues; Toxic effect; Translations; Traumatic Brain Injury; Uridine; Vascular Permeabilities; Veterans; Walking; Water; Work; attenuation; central nervous system injury; chemokine; chronic neurologic disease; chronic neuropathic pain; chronic pain; cytokine; cytotoxic; cytotoxicity; disability; functional improvement; functional outcomes; glial activation; improved; improved outcome; inflammatory milieu; inhibitor; inhibitor therapy; injured; injury recovery; innovation; insight; mRNA Stability; migration; monocyte; motor recovery; nerve injury; neuroinflammation; neuron loss; neuroprotection; neutrophil; new therapeutic target; novel; overexpression; painful neuropathy; posttranscriptional; preclinical study; protein expression; prototype; recruit; response; severe injury; small molecule; small molecule inhibitor; therapeutic target; tissue injury; transgene expression; vasogenic edema; white matter

Spinal cord injury (SCI) is devastating and most often affects younger Veterans. There is significant long-term morbidity, a shortened life span, and a high financial burden. Because of the poor regenerative capacity of the spinal cord, development of early interventions that minimize secondary tissue injury is a priority. A major contribution to secondary tissue damage and the initiation of neuropathic pain is the inflammatory cascade triggered by activated glial cells (microglia and astroglia). This cascade begins immediately after SCI with glial release of cytokines, reactive species, and vasoactive substances. This secretome produces damage to neurons, oligodendrocytes and other cells at and beyond the level of injury through direct cytotoxic mechanisms or indirectly through the promotion of cytotoxic and vasogenic edema, vascular compromise, and tissue ischemia. These inflammatory mediators also trigger pathways that lead to chronic pain. The inflammatory cascade is further accelerated by glial production of chemokines which recruit peripheral immune cells, including neutrophils and monocytes, within the acute phase of injury. A major driver of the initial glial response is HuR, an RNA regulator that promotes expression of key inflammatory mediators through posttranscriptional mechanisms. Inflammatory mediators such as IL-1β, IL-6, TNF-α and iNOS contain adenine- and uridine-rich elements in the 3’ untranslated region (ARE) to which HuR binds and positively regulates their expression. Our prior work in SCI shows that HuR is activated in the acute phase of SCI and exacerbates injury when overexpressed in glia. Our team has developed a novel class of small molecule HuR inhibitors that blocks induction of inflammatory mediators in glial cells. In a pilot study of SCI using a mid- thoracic contusion model, we observed attenuation of clinical deficits and neuronal loss with the prototype HuR inhibitor, SRI-42127. We also found that SRI-42127 reduced allodynic pain in a peripheral nerve injury model. In this proposal we hypothesize that HuR drives expression of a pro-inflammatory and toxic secretome by resident glia that is triggered in the early stages of SCI, and that inhibiting HuR will reduce secondary tissue injury, improve motor outcome and reduce neuropathic pain. We propose 3 specific aims: (1) Further characterize the beneficial effect of HuR inhibition by SRI-42127on SCI recovery, (2) Assess mechanisms by which HuR inhibition improves recovery after SCI, and (3) Assess the contribution of glial HuR to inflammatory responses and tissue injury in SCI. The long term objectives of this proposal are to advance our small molecule HuR inhibitors as a therapy in acute SCI and to gain a mechanistic understanding of how ARE-mediated post-transcriptional regulation impacts SCI (secondary tissue injury, motor recovery and neuropathic pain). The innovation of this proposal is the investigation of a novel class of HuR inhibitors for therapeutically targeting the acute inflammatory response in SCI and the mechanistic investigation of post- transcriptional pathways (to date essentially unexplored) in SCI. The significance of this application is its focus on a treatment approach that might eventually be used in the battlefield at the time of acute injury as our preclinical studies indicate excellent and fast penetration of SRI-42127 into the central nervous system with peripheral administration, and a mitigating effect on neuronal loss and neuropathic pain. The signfiicance extends beyond SCI as the same HuR-regulated pathways drive neuroinflammation in other acute CNS injuries (e.g. traumatic brain injury or stroke) and chronic neurological diseases (e.g. ALS and Alzheimers).

脊髓损伤（SCI）是毁灭性的，最常影响年轻的退伍军人。长期有重大的 发病率，寿命缩短和高金融伯恩伯恩（Burnen）。由于再生能力不佳 脊髓，最小化次级组织损伤的早期干预措施的发展是当务之急。专业 对次要组织损伤和神经性疼痛的倡议的贡献是炎症级联 由活化的神经胶质细胞（小胶质细胞和星形胶质细胞）触发。该级联在Sci后立即开始使用Glial 细胞因子，反应性物种和血管活性物质的释放。这个秘密对 神经元，少突胶质细胞和其他细胞通过直接细胞毒性在损伤水平上 通过促进细胞毒性和血管水肿，血管损害和间接的机制或间接 组织缺血。这些炎症介质还触发导致慢性疼痛的途径。这 趋化级联反应通过趋化因子的神经胶质产生进一步加速 在损伤的急性期内，包括中性粒细胞和单核细胞在内的细胞。最初神经胶质的主要驱动力 响应是HUR，这是一种RNA调节剂，可通过 转录后机制。 IL-1β，IL-6，TNF-α和Inos等炎症介质包含 在3'非翻译区域（HUR）与HUR绑定并积极的3'非翻译区域中的腺嘌呤和尿苷富含元素 调节他们的表达。我们先前在SCI中的工作表明，HUR在SCI的急性阶段被激活 在神经胶质中过表达时会加剧伤害。我们的团队已经开发了一个新颖的小分子hur 阻断神经胶质细胞中炎症介质诱导的抑制剂。在一项使用中期的SCI的试点研究中 胸部挫伤模型，我们观察到与原型HUR的临床缺陷和神经元丧失的衰减 抑制剂，SRI-42127。我们还发现，SRI-42127在周围神经损伤模型中减少了异肌疼痛。 在此提案中，我们假设HUR驱动了促炎和有毒的分泌组的表达 在SCI早期触发的居民神经胶质的作用，抑制HUR将减少 次要组织损伤，改善运动结果并减轻神经性疼痛。我们提出了3个特定的 目的：（1）进一步描述了通过SRI-42127ON SCI恢复对HUR抑制的有益作用，（2）评估 HUR抑制可改善SCI后恢复的机制，以及（3）评估Glial hur的贡献 炎症反应和SCI的组织损伤。该提议的长期目标是提高 我们的小分子HUR抑制剂作为急性SCI的一种疗法，并获得机械理解 介导的转录后调节会影响SCI（次要组织损伤，运动恢复和 神经性疼痛）。该提案的创新是一种新颖的HUR抑制剂投资 治疗以SCI中的急性炎症反应和后的机械投资靶向治疗 SCI中的转录途径（迄今为止本质上是意外的）。该应用的重要性是 专注于一种治疗方法，该方法最终可能在急性受伤时在战场上使用 临床前研究表明，SRI-42127在中枢神经系统中出色而快速渗透 外围给药，以及对神经元丧失和神经性疼痛的缓解作用。标志性 超越SCI，因为相同的HUR调节途径驱动其他急性中枢神经系统的神经炎症 损伤（例如脑损伤或中风）和慢性神经系统疾病（例如ALS和Alzheimers）。