Elucidating the role of miR-155 in the development of paralysis consecutive to spinal cord damage caused by thoracic-abdominal aortic aneurysm repair surgery

阐明 miR-155 在胸腹主动脉瘤修复手术引起的脊髓损伤后瘫痪发展中的作用

• 批准号: 9375175
• 负责人: Esmerina Tili
• 金额: $ 7.75万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9375175
• 关键词: Abdominal Aortic Aneurysm; Ablation; Affect; Aortic Aneurysm; Blood - brain barrier anatomy; Brain; Cell Compartmentation; Cerebrospinal Fluid; Charge; Chest; Choline O-Acetyltransferase; Chronic; Clinical Trials; Closure by clamp; Complement; Complication; Data; Development; Docosahexaenoic Acids; Edema; Endothelial Cells; Enterobacteria phage P1 Cre recombinase; Fright; Functional disorder; Gene Targeting; Genes; Goals; Hindlimb; Hour; Human; Impairment; Inflammation; Inflammatory; Injury; Ischemia; Knock-in; Knock-in Mouse; Knock-out; Knockout Mice; Leg; Light; Maintenance; Malignant Neoplasms; Measures; MicroRNAs; Modeling; Molecular; Motor Neurons; Mouse Strains; Mus; Neurons; Omega-3 Fatty Acids; Operative Surgical Procedures; Paralysed; Paraplegia; Pathology; Patients; Pharmacologic Substance; Pharmacology; Phosphotransferases; Prevention; Prevention strategy; Preventive; Production; Regulator Genes; Risk; Role; Spinal Cord; Spinal cord damage; Spinal cord grey matter structure; Stroke; Therapeutic; Transcript; Transgenes; Traumatic Brain Injury; Tyrosine; Untranslated RNA; Vascular blood supply; cytokine; design; gray matter; improved; mouse model; neurovascular unit; novel; novel therapeutics; overexpression; pre-clinical; promoter; repaired; transcriptome

PROJECT SUMMARY The most feared, unpredictable complication of thoracic-abdominal aortic aneurysm (TAAA) repair surgery is paraplegia caused by ischemic injury to the spinal cord (SC). There is urgency to identify new molecules that would complement existent, non-pharmacological preventive strategies. With this aim, we have developed a mouse model of TAAA where aortic cross-clamping (ACC) results in the development of central cord edema, gray matter damage, and delayed hind-limb paralysis. MicroRNA 155 (miR-155), a short non-coding RNA that negatively regulates the expression of a number of target transcripts, has been involved in pathologies such as chronic inflammation and cancer. Using our mouse model, we have found that miR-155 expression increases in motoneurons and endothelial cells of the SC following ACC. In addition, we have established that the ablation of the miR-155 gene limits the development of central cord edema, reduces the extent extend of SC gray matter damage, and decreases the rate of paralysis by 40%. We further found that, in ischemic SC, miR-155 targets Mfsd2a transcripts directly. Mfsd2a encodes a transporter in charge of supplying neurons with the indispensable omega-3 polyunsaturated docosahexaenoic (DHA) acid. Mfsd2a is also critical for the maintenance of the integrity of blood-brain barrier. These data suggest that miR-155 might target a number of transcripts and have compounding deleterious effects in the different compartments of the neurovascular unit. Therefore, we propose two complementary approaches to analyze miR-155 specific effects in endothelial cells and motoneurons. First, we will analyze the consequences on edema development, gray matter damage and paralysis of specifically deleting miR-155 in endothelial cells or motoneurons in our mouse ACC model. Secondly, mice that specifically overexpress miR-155 in either endothelial cells or motoneurons will be used for transcriptome analyses in order to identify miR-155 critical targets in these two cell compartments in normal, non ischemic conditions. At the end of this study, we anticipate to have identified the most critical targets of miR-155 in endothelial cells and motoneurons. These data will help to design new drugs aimed at combining the normalization of the expression of miR-155 and of its critical target transcripts in ischemic SC. Given that microRNA-directed therapies are now on clinical trials, we believe that our study holds great translational potentials not only for the prevention of paraplegia after TAAA repair surgery, but also for the treatment of neuronal ischemia due to stroke or SC/brain traumatic injuries where deleterious effects of miR-155 take place.

项目总结 胸腹主动脉瘤(Taaa)修补术最可怕、最不可预测的并发症是 脊髓(SC)缺血性损伤引起的截瘫。迫切需要识别新的分子， 将补充现有的非药理学预防策略。本着这个目标，我们开发了一种 主动脉阻断(ACC)导致中央脊髓水肿的小鼠TAAA模型， 灰质损伤和延迟性后肢瘫痪。MicroRNA 155(miR-155)，一种短的非编码RNA， 负向调节一些靶转录本的表达，参与了多种病理过程 慢性炎症和癌症。 使用我们的小鼠模型，我们发现miR-155在运动神经元和内皮细胞中的表达增加 ACC后的SC细胞。此外，我们已经证实，miR-155基因的消融限制了 中央脊髓水肿的发生，减少了SC灰质损害的范围，并减少了 瘫痪的比率为40%。我们进一步发现，在缺血SC中，miR-155直接靶向Mfsd2a转录本。 Mfsd2a编码一个转运蛋白，负责向神经元供应不可或缺的omega-3多不饱和脂肪酸。 二十二碳六烯酸(DHA)。Mfsd2a对维持血脑屏障的完整性也至关重要。 这些数据表明miR-155可能针对一些转录本，并具有复合有害作用 在神经血管单位的不同间隔中的作用。因此，我们提出了两个互补的 分析miR-155对内皮细胞和运动神经元的特异性作用的方法。首先，我们将 分析特定缺失对水肿发展、灰质损伤和瘫痪的影响 在我们的小鼠ACC模型中，MIR-155在内皮细胞或运动神经元中表达。第二，特定的小鼠 在内皮细胞或运动神经元中过表达的miR-155将用于转录组分析 为了在正常和非缺血的这两个细胞室中识别miR-155关键靶点 条件。 在这项研究结束时，我们预计已经确定了miR-155在内皮细胞中最关键的靶点。 还有运动神经元。这些数据将有助于设计新的药物，旨在结合 MiR-155及其关键靶向转录本在缺血SC中的表达鉴于这种由microRNA引导的 治疗方法现在正在进行临床试验，我们相信我们的研究具有巨大的翻译潜力，不仅适用于 预防截瘫后的TAAA修复手术，也用于治疗因神经元缺血引起的 发生miR-155有害影响的中风或SC/脑创伤。