A Novel Model of Intracranial Aneurysm to Guide Development of Less Invasive Therapies

项目总结/摘要 中风每40秒发生一次，是导致长期残疾的主要原因，也是导致残疾的第五大原因。 美国人的死亡。虽然缺血性卒中占卒中事件的大多数（约87%）， 出血性中风，或由于血管破裂或变弱而出血引起的中风， 约40%的中风相关死亡1。这些统计数据对于那些被诊断患有颅内动脉瘤的人来说是可怕的 （ICA），因为在大多数情况下，机械器械治疗的风险远远超过保守治疗的风险。 监测.对导致脑动脉瘤生长的细胞机制知之甚少 和有限的手段来检测增长的变化，临床医生留下了复杂的决定，如何管理 病人护理我的目标是探索控制ICA进展的机制，并开始开发一个 使用新的体外模型系统的侵入性更小的治疗选择。目前的动物模型或者利用 外周血管系统，与颅内血管缺乏解剖学相似性，或在 啮齿类动物，这限制了临床级基于导管的治疗剂的测试。我们目前正在验证一个 伊卡的犬模型，解决了这些问题，将在本奖学金开始时完成。作为动物 模型是昂贵的、时间密集的，因此难以用于参数优化， 需要大的样本量，开发伊卡的体外模型也至关重要。该提案旨在发展 并利用该模型来优化用于递送旨在钝化的治疗剂的参数 炎症和稳定血管壁。为此，我们将采用生物材料表面改性、3D 打印和4D流磁共振成像（MRI），以开发和验证患者特定的模型， 伊卡旨在概括血管的机械特性，以施加患者特定的血液 流动概况（由合作者确定），并将内皮细胞纳入研究机制， 内皮细胞活化（Aim 1）。这个模型将使我们能够测试针对以下机制的治疗方法： 动脉瘤进展，主要是旨在淬灭内皮细胞活化的疗法。这导致具体 目的2，利用体外模型优化和测试间充质干细胞的潜力， 稳定囊内的内皮细胞。这项研究将为更复杂的 根据患者数据建立的体外模型，也将导致侵入性较小的临床前和临床试验。 ICA的治疗方法。最终目标是为临床医生和患者提供更好的选择， 为研究人员提供了一个研究伊卡的新平台 动力学建议的工作将伴随着一个专门为我设计的培训计划，其中包括 通过教学讲座进行广泛的神经科学教育，重点关注神经血管病理学， 辅以神经外科团队的临床和实践培训，每周病例报告，以及 手术观察

PROJECT SUMMARY/ABSTRACT A stroke occurs every 40 seconds and is a leading cause of long-term disabilities and the 5th leading cause of death for Americans. Although ischemic strokes account for the majority (~87%) of incidents of stroke, hemorrhagic strokes, or strokes as a result of bleeding from a ruptured or weakened blood vessel, account for ~40% of stroke-related deaths1. These statistics are terrifying for those diagnosed with intracranial aneurysms (ICAs) as in most cases the risk of treatment with a mechanical device far outweighs the risk of conservative monitoring. With very little known about the cellular mechanisms that contribute aneurysm growth in the brain and limited means to detect changes in growth, clinicians are left with the complex decision of how to manage patient care. My goal is to probe the mechanisms that govern the progression of ICAs and begin to develop a less invasive therapeutic option using a new in vitro model system. Current animal models either utilize the peripheral vasculature, which lacks anatomical similarities to intracranial vessels, or are implemented in rodents, which limit the testing of clinical grade, catheter-based therapeutics. We are currently validating a canine model of ICA that addresses these issues that will be complete at the start of this fellowship. As animal models are expensive, time intensive and therefore challenging to utilize for parameter optimizations that require large sample sizes, it is also crucial to develop an in vitro model of ICA. This proposal seeks to develop such a model and utilize the model to optimize parameters for delivery of a therapeutic intended to blunt inflammation and stabilize the vessel wall. To this end, we will use biomaterials surface modification, 3D printing and 4D-flow magnetic resonance imaging (MRI) to develop and validate a patient-specific model of ICA that aims to recapitulate the mechanical properties of the blood vessels, to impose patient-specific blood flow profiles (as determined by collaborators) and to incorporate endothelial cells to study mechanisms of endothelial cell activation (Aim 1). This model will allow us to test therapeutics that target the mechanisms of aneurysm progression, mainly therapies designed to quench endothelial cell activation. This leads to Specific Aim 2, which will utilize the in vitro model to optimize and test the potential of mesenchymal stem cells to stabilize endothelial cells within the aneurysmal sac. This research will lay the foundation for more complex in vitro models that are informed by patient data, and will also lead to preclinical and clinical trials of less invasive therapeutics for ICAs. The end goal is to provide clinicians and patients with better options for safely treating those affected with this devastating disease and to provide researchers with a new platform for studying ICA dynamics. The proposed work will be accompanied by a training plan designed specially for me that includes extensive education in neuroscience with a focus on neurovascular pathology via didactic lectures, supplemented with clinical and hands on training with a neurosurgical team, weekly case presentations, and surgical observation.