Identifying effective therapies to prevent paralysis after aortic aneurysm repair surgery

确定预防主动脉瘤修复手术后瘫痪的有效疗法

• 批准号: 9809805
• 负责人: Hamdy M. Elsayed-Awad
• 金额: $ 42.9万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9809805
• 关键词: Abdominal Aortic Aneurysm; Animal Model; Animals; Anti-inflammatory; Antiinflammatory Effect; Antisense Oligonucleotides; Aortic Aneurysm; Apoptotic; Award; Blood; Blood - brain barrier anatomy; Brain; Canis familiaris; Chest; Closure by clamp; Complement; Complication; Data; Development; Diagnosis; Docosahexaenoic Acids; Edema; Endothelial Cells; Endothelium; Extravasation; Fright; Functional disorder; Future; Genes; Hindlimb; Homeostasis; Impairment; Inflammation; Inflammatory; Injury; Intravenous; Ischemia; MAPK8 gene; Maintenance; Measures; Membrane; MicroRNAs; Modeling; Molecular; Motor Neurons; Mus; N-terminal; Neurons; Omega-3 Fatty Acids; Operative Surgical Procedures; Paralysed; Paraplegia; Pathology; Patients; Pharmacology; Phospholipids; Phosphotransferases; Pilot Projects; Prevention strategy; Preventive; Preventive Intervention; Preventive therapy; Preventive treatment; Production; Publishing; RNA; Rattus; Recovery of Function; Spinal Cord; Spinal cord damage; Spinal cord injury; Surface; Testing; Therapeutic; Thoracic aorta; Transcription Factor AP-1; United States; Untranslated RNA; Up-Regulation; Vascular blood supply; Wild Type Mouse; Work; base; effective therapy; experience; gray matter; improved; inhibitor/antagonist; intraperitoneal; mouse model; neuroinflammation; novel; pre-clinical; prevent; promoter; protective effect; repaired; standard of care; stroke model

PROJECT SUMMARY Approximately 24,000 new cases of thoraco-abdominal aortic aneurysms (TAAAs) are diagnosed each year in the USA. The most feared complication of TAAA open repair is paraplegia (5-10% of patients) caused by ischemic spinal cord (SC) injury following surgery. Therefore, there is urgency to identify new molecules that would complement existent, non-pharmacological preventive strategies. With this aim, we developed a mouse and a dog model of TAAA open repair where aortic cross-clamping (ACC) results in central cord edema, gray matter damage, and hindlimb paralysis. MicroRNAs are short, non-coding RNAs that negatively regulate the expression of multiple target genes and have been implicated in a number of pathologies. We have shown that miR-155, a microRNA established by us and others to be highly pro-inflammatory, is causal in inducing exacerbated inflammation that leads to blood-SC barrier leakage, central cord edema development, gray matter damage, and paralysis. Namely, we found that mice with miR-155 global deletion present a rate of paralysis 62.5% of that of wild-type mice, associated with reduced gray matter damage. In addition, we found that, under ischemic conditions, miR-155 impairs the expression of Mfsd2a (Major facilitator superfamily domain containing 2a), a gene that encodes an endothelial transporter of omega-3 docosahexaenoic acid (DHA, 22:6n-3) that is also implicated in the maintenance of the integrity of the blood- brain barrier. Importantly, the brain, whose phospholipids contain 15% of DHA, however cannot synthesize this compound and therefore needs a constant supply of it. DHA is key for both the function of the brain and the production of powerful anti-inflammatory derivatives (docosanoids and elovanoids) that are critical to brain homeostasis. Accordingly, we found that the SC of non-paralyzed mice express Mfsd2a levels significantly higher than paralyzed mice after ACC. Therefore, we propose two independent approaches to reduce the rate of paralysis following ischemia: (1) Directly blocking miR-155 deleterious activity using a miR-155 antisense oligonucleotide; and (2) Increasing DHA supply to the SC. Both treatments will impair the development of local and systemic inflammation, reduce the development of central cord edema and gray matter damage, and consequently decrease the rate of paralysis. While miR-155 and DHA effects has been previously studied in stroke models, thus providing strong ground for our strategies, they were never tested in our mouse ACC model. As TAAA repair follows a programmed surgical procedure, providing a window of opportunity for preventive intervention, our strategies hold a strong translational potential in TAAA open repair surgery. In the future, they could also be tested in our canine and mouse models (under development) of endovascular aortic repair.

项目总结 每年约有24,000例新的胸腹主动脉瘤(TAAA)被诊断出来 美国。TAAA开放修补术最可怕的并发症是由以下原因引起的截瘫(5%-10%的患者) 手术后脊髓(SC)缺血性损伤。因此，迫切需要确定新的分子 将补充现有的非药理学预防策略。在这个目标下，我们开发了一种 小鼠和狗的开放修补模型，其中主动脉交叉阻断(ACC)导致中央脊髓 浮肿，灰质受损，后肢瘫痪。 MicroRNAs是一种短的、非编码的RNA，它负向调节多个靶基因的表达，并 已经牵涉到许多病理过程中。我们已经证明，miR-155，一种由 美国和其他国家高度促炎，是导致炎症加剧的原因，从而导致 血-干细胞屏障渗漏，中央脊髓水肿发展，灰质损伤，瘫痪。也就是说，我们 发现miR-155全局缺失的小鼠的瘫痪发生率是野生型小鼠的62.5%， 与减少灰质损伤有关。 此外，我们还发现，在缺血条件下，miR-155损害了Mfsd2a(主要 包含2a)的促进剂超家族结构域，该基因编码omega-3的内皮转运蛋白 二十二碳六烯酸(DHA，22：6N-3)，也与维持血液完整性有关- 大脑屏障。重要的是，大脑的磷脂中含有15%的DHA，但是大脑不能合成DHA 化合物，因此需要持续的供应。DHA对大脑和大脑的功能都很重要 产生对大脑至关重要的强大的抗炎衍生物(二十二碳二烯和二十二碳二烯) 动态平衡。相应地，我们发现非瘫痪小鼠的SC显著表达Mfsd2a水平 高于ACC后瘫痪小鼠。 因此，我们提出了两种独立的方法来降低缺血后的瘫痪比率： (1)用miR-155反义寡核苷酸直接阻断miR-155的有害活性； 增加对SC的DHA供应。这两种治疗方法都会损害局部和全身的发展 炎症，减少中央脊髓水肿和灰质损伤的发展，从而 降低瘫痪发生率。 虽然miR-155和DHA效应之前已经在中风模型中进行了研究，因此为 我们的策略，它们从未在我们的小鼠ACC模型中进行过测试。因为taaa修复遵循程序 手术过程，为预防性干预提供了机会之窗，我们的策略掌握着强大的 TAAA开放修复术的翻译潜力。在未来，它们也可以在我们的狗身上进行测试 主动脉腔内修复的小鼠模型(正在开发中)。