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.

项目概要 本研究的主要目标是研究肉毒杆菌毒素 A (BTX A) 肾上腺素能和 Rho 的影响 激酶途径首次阐明其在人脑中的解痉作用机制 血运重建移植物。血运重建移植物狭窄和闭塞仍然是一个可怕的并发症， 可导致显着的发病率和死亡率。血管痉挛引起的移植物狭窄和闭塞被认为是 至少部分是通过肾上腺素能血管痉挛途径的活性增加介导的。另外，证据 已经描述了支持 RhoA/Rho 激酶 (ROCK) 通路在血管痉挛中的作用。尽管有各种 建议使用解痉剂，目前尚无单一有效药物。包括解剖学和生理学变异性在内的因素 在血运重建导管中，患者人口统计学和合并症与移植物相关 血管痉挛的发病机制和对解痉药的反应。鉴于这些知识，理想的解痉剂可能 需要调节多种途径才能发挥治疗作用。 BTX A 是一种强效神经毒素，在临床实践中广泛用于治疗多种痉挛病症。 尽管其胆碱能神经传递阻断的经典范例已被广泛接受，但证据 对于其他可能的机制已经进行了描述。其他涉及肾上腺素能调节的机制， ROCK 和内皮血管舒缩通路已在动物研究中得到报道。近日，我们课题组发表了 第一个试点研究描述了使用 BTX A 预防脑血管重建移植物痉挛。 拟议的研究将利用 BTX A 治疗前后收集的剩余动脉组织样本 脑血管搭桥手术。我们最近成立了一个机构审查委员会，批准了新的- 冷冻血管组织库，用于储存血管组织样本并可检索用于研究 目的。 BTX A 对两种主要血管痉挛作用的靶向组织、蛋白质和分子水平分析 途径将利用我们机构附属的核心设施和研究实验室进行。 阐明 BTX A 解痉作用的作用机制将有助于填补目前之间的知识空白 人体和动物研究，可以为二期临床疗效研究提供基础。这些发现还 有潜力扩大 BTX A 在心脏血运重建中血管痉挛并发症的应用 重建手术。我们的基础科学合作、血管组织库和大量临床研究使 我们的脑血运重建中心为开展这项研究提供了独特的环境。