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

项目摘要/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 美国人的死亡。虽然缺血性中风占中风事件的大部分(~87%)， 出血性中风，或由破裂或虚弱的血管出血引起的中风，占 约40%与中风有关的死亡1。这些统计数据对那些被诊断为颅内动脉瘤的人来说是可怕的。 (ICAS)在大多数情况下，使用机械装置治疗的风险远远超过保守治疗的风险 监控。对导致脑内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，临床医生面临着如何管理的复杂决定 病人护理。我的目标是探索管理ICAS进展的机制，并开始开发一种 使用新的体外模型系统进行侵入性较小的治疗选择。目前的动物模型要么利用 外周血管系统，在解剖学上与颅内血管缺乏相似性，或在 啮齿动物，这限制了临床分级、基于导管的治疗方法的测试。我们目前正在验证 ICA的犬类模型，解决这些问题，这些问题将在此团契开始时完成。作为动物 模型昂贵、时间密集，因此要用于参数优化具有挑战性 除了需要大样本量外，开发ICA的体外模型也是至关重要的。这项建议旨在发展 这样的模型，并利用该模型来优化参数，用于输送意欲钝化的治疗 消炎和稳定血管壁。为此，我们将使用生物材料表面改性，3D 打印和4D-Flow磁共振成像(MRI)，以开发和验证患者特定的模型 ICA，旨在概括血管的机械特性，以施加患者特定的血液 血流分布(由合作者确定)，并结合内皮细胞来研究 内皮细胞激活(目标1)。这一模型将使我们能够测试针对以下机制的疗法 动脉瘤进展，主要是旨在抑制内皮细胞激活的治疗。这导致了具体的 目的2，将利用体外模型优化和测试间充质干细胞 稳定动脉瘤囊内的内皮细胞。这项研究将为更复杂的 由患者数据提供信息的体外模型，也将导致侵入性较小的临床前和临床试验 ICAS的治疗学。最终目标是为临床医生和患者提供更好的安全治疗选择。 并为研究人员提供研究ICA的新平台 动力学。拟议的工作将伴随着专门为我设计的培训计划，其中包括 广泛的神经科学教育，通过授课讲授神经血管病理学， 辅以神经外科团队的临床和动手培训，每周病例介绍，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.