Elucidation of botulinum neurotoxin A mediated cerebral revascularization graft spasmolysis mechanisms

阐明肉毒杆菌神经毒素 A 介导的脑血运重建移植物解痉机制

• 批准号: 9810060
• 负责人: Jonathan Joseph Russin
• 金额: $ 8.25万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9810060
• 关键词: Adrenergic Agents; Anatomy; Aneurysm; Animals; Area; Basic Science; Blood Vessels; Blood flow; Botulinum Toxin Type A; Brain; Bypass; Cardiac; Cerebral Revascularization; Cleaved cell; Clinical; Collaborations; Comorbidity; Complication; Core Facility; Endothelium; Environment; Freezing; Goals; Human; Immunohistochemistry; Institution; Institutional Review Boards; Ischemia; Knowledge; Laboratory Research; Lead; Measurement; Mediating; Molecular; Molecular Biology Techniques; Morbidity - disease rate; Myosin Light Chains; Nerve; Neurotoxins; Norepinephrine; Obstruction; Operative Surgical Procedures; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Physiological; Pilot Projects; Postoperative Period; Prevention; Proteins; Publishing; Quantitative Reverse Transcriptase PCR; Reconstructive Surgical Procedures; Reporting; Research; Rho-associated kinase; Risk; Role; Sampling; Spasm; Spasmolytics; Specimen; Stenosis; Stroke; Synaptic Transmission; System; Therapeutic Effect; Time; Tissue Banks; Tissue Grafts; Tissue Sample; Tissues; Tunica Adventitia; Tyrosine 3-Monooxygenase; Vasomotor; Vasospasm; Western Blotting; cerebrovascular; cholinergic; clinical efficacy; clinical practice; demographics; efficacy study; liquid chromatography mass spectrometry; mRNA Expression; mortality; myosin phosphatase; novel; receptor; recruit; response; revascularization surgery; spasticity; synaptosomal-associated protein 25; tumor

Project Summary The primary goal of this study is to investigate the effects of botulinum toxin A (BTX A) adrenergic and Rho kinase pathways elucidating, for the first time, its spasmolytic mechanism of action in human cerebral revascularization grafts. Revascularization graft stenosis and occlusion remains a formidable complication which can lead to significant morbidity and mortality. Graft stenosis and occlusion from vasospasm is thought to be at least partially mediated through increased activity in adrenergic vasospastic pathways. Additionally, evidence supporting the role of the RhoA/Rho kinase (ROCK) pathway in vasospasm has been described. Despite various proposed spasmolytics, there is no single effective agent. Factors including anatomic and physiologic variability in revascularization conduits, patient demographics and comorbidities have been associated with graft vasospasm pathogenesis and response to spasmolytics. Given this knowledge, the ideal spasmolytic agent likely needs to modulate multiple pathways to exert therapeutic effect. BTX A is a powerful neurotoxin widely used in clinical practice for the treatment of a variety of spastic conditions. Although its classic paradigm of cholinergic neural transmission blockade has been widely accepted, evidence for other possible mechanisms has been described. Other mechanisms involving modulation of adrenergic, ROCK and endothelial vasomotor pathways has been reported in animal studies. Recently, our group published the first pilot study describing use of BTX A for cerebral revascularization graft spasm prevention. The proposed study will utilize leftover arterial tissue samples collected pre- and post-BTX A treatment during cerebrovascular bypass surgery. We have recently established an Institutional Review Board approved fresh- frozen vascular tissue bank where the vascular tissue samples are stored and can be retrieved for research purposes. Targeted tissue, protein and molecular level analyses of BTX A effects on two major vasospastic pathways will be performed utilizing core facilities and research laboratories affiliated with our institution. Elucidating the mechanism of action for BTX A spasmolysis will help to fill a current gap in knowledge between human and animal studies and could provide the basis for a phase 2 clinical efficacy study. These findings also have the potential to expand the use of BTX A for vasospastic complications in cardiac revascularization and reconstructive surgery. Our basic science collaborations, vascular tissue bank and high clinical volume make our Cerebral Revascularization center a unique environment to perform this research.

项目摘要 这项研究的主要目的是研究肉毒杆菌毒素A（BTX A）肾上腺素和RHO的影响 激酶途径首次阐明其在人脑中的痉挛性作用机理 血运重建移植物。血运重建移植狭窄和阻塞仍然是一种强大的并发症， 可能导致明显的发病率和死亡率。血管痉挛的移植狭窄和闭塞被认为是 通过在肾上腺素能血管痉挛途径中的活性增加而介导的最低介导。另外，证据 已经描述了支持RhoA/Rho激酶（岩石）途径在血管痉挛中的作用。尽管有很多 提出的痉挛性，没有单一有效的药物。包括解剖和生理变异的因素 在血运管道中，患者人口统计和合并症与移植有关 血管痉挛的发病机理和对痉挛的反应。鉴于这些知识，理想的痉挛剂可能 需要调节多种途径以发挥治疗作用。 BTX A是一种强大的神经毒素，在临床实践中广泛用于治疗各种痉挛状况。 尽管其经典的胆碱能神经传递封锁范围已被广泛接受，但证据 对于其他可能的机制，已经描述了。其他涉及肾上腺素能调节的机制 在动物研究中，已经报道了岩石和内皮血管舒缩途径。最近，我们的小组出版了 第一项描述BTX A用于预防脑血运重建痉挛的试验研究。 拟议的研究将利用剩余的动脉组织样本在BTX前后收集的治疗 脑血管旁路手术。我们最近建立了一个机构审查委员会批准的新鲜 - 冷冻的血管组织库存储了血管组织样品，可以检索进行研究 目的。 BTX A对两个主要血管腔的影响的靶向组织，蛋白质和分子水平分析 利用与我们机构相关的核心设施和研究实验室，将进行途径。 阐明BTX的作用机理痉挛性将有助于填补当前知识之间的差距 人类和动物研究，可以为2期临床疗效研究提供基础。这些发现也是如此 有可能扩大BTX A用于血管痉挛并发症的心脏血运重建和 重建手术。我们的基础科学合作，血管组织库和高临床量使 我们的脑血运重建为进行这项研究的独特环境。