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.

项目摘要 胸腹主动脉瘤（TAAA）修复手术最令人担忧，最不可预测的并发症是 由脊髓缺血性损伤引起的截瘫（SC）。有迫切需要识别新分子 是否存在补充，非药理学预防策略。以这个目的，我们开发了 TAAA的小鼠模型，主动脉互夹（ACC）导致中央脐带水肿的发展， 灰质损害和后杆瘫痪延迟。 microRNA 155（mir-155），一种短的非编码RNA 负面调节许多靶转录本的表达，已经参与了诸如 慢性炎症和癌症。 使用鼠标模型，我们发现MiR-155表达在运动神经元和内皮中增加 ACC之后的SC细胞。此外，我们已经确定miR-155基因的消融限制了 中央脐带水肿的发展，减少了SC灰质损害的范围，并减少了 瘫痪率增加40％。我们进一步发现，在缺血性SC中，miR-155靶向MFSD2A转录本。 MFSD2A编码负责为神经元提供必不可少的omega-3多不饱和的转运蛋白 Docosahexaenoic（DHA）酸。 MFSD2A对于维持血脑屏障的完整性也至关重要。 这些数据表明，miR-155可能针对许多成绩单，并且具有复杂的有害 在神经血管单元的不同隔室中的影响。因此，我们提出了两个补充 分析内皮细胞和运动神经元中miR-155特异性效应的方法。首先，我们会的 分析对水肿发展，灰质损害和瘫痪的后果 在我们的小鼠ACC模型中，内皮细胞或运动神经元中的miR-155。其次，小鼠特别 内皮细胞或运动神经元中的过表达miR-155将用于转录组分析 为了在正常的非缺血性中识别这两个细胞室中的miR-155关键靶标 状况。 在这项研究结束时，我们预计将确定内皮细胞中miR-155的最关键靶标 和运动神经元。这些数据将有助于设计旨在结合标准化的新药 miR-155及其关键靶标转录物在缺血性SC中的表达。鉴于该microRNA定向 疗法现在正在临床试验中，我们认为我们的研究不仅具有巨大的翻译潜力 TAAA修复手术后的预防截瘫，但也用于治疗因神经元缺血而引起的 MiR-155发生有害影响的中风或SC/脑外伤性损伤。