Elucidation of botulinum neurotoxin A mediated cerebral revascularization graft spasmolysis mechanisms

项目摘要 本研究的主要目的是探讨A型肉毒毒素(BTX-A)、肾上腺素能和Rho的作用。 首次阐明了其在人脑中的解痉性作用机制 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 可能导致严重的发病率和死亡率。血管痉挛引起的移植物狭窄和闭塞被认为是在 至少部分通过肾上腺素能血管痉挛通路的活性增加而起作用。此外，有证据表明 支持RhoA/Rho激酶(ROCK)通路在血管痉挛中的作用已被描述。尽管有各种各样的 建议的解痉剂，目前还没有单一的有效药物。包括解剖和生理变异在内的因素 在血运重建管道中，患者的人口统计和合并症与移植物有关。 血管痉挛的发病机制和对解痉剂的反应。有了这些知识，理想的解痉剂很可能 需要调节多个通路才能发挥治疗作用。 BTX A是一种强大的神经毒素，广泛用于临床治疗各种痉挛状态。 尽管其经典的胆碱能神经传递阻断范式已被广泛接受，但有证据表明 对于其他可能的机制也进行了描述。其他涉及肾上腺素能调节的机制， ROCK和内皮血管运动通路已在动物研究中被报道。最近，我们小组发表了 第一项试验性研究描述了使用BTX A预防脑血管重建移植物痉挛。 拟议的研究将利用在BTX A治疗前和治疗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- 用于存储血管组织样本并可检索用于研究的冷冻血管组织库 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 路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A型BTX痉挛的作用机制将有助于填补目前知识上的空白 人类和动物研究，并可为第二阶段临床疗效研究提供基础。这些发现还包括 有潜力扩大BTX A在心脏血管重建和血管重建中血管痉挛并发症的使用 整形手术。我们的基础科学合作、血管组织库和高临床容量使 我们的大脑血管重建中心有一个独特的环境来进行这项研究.

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.