Development of a 3D neurovascular unit for in vitro modeling of subarachnoid hemorrhage and screening therapies

开发用于蛛网膜下腔出血体外建模和筛选治疗的 3D 神经血管单元

基本信息

批准号：
10722387
负责人：
Brian J O'Grady
金额：
$ 11.29万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10722387
关键词：
3-Dimensional 3D Print Ablation Address Affect Age Anatomy Aneurysmal Subarachnoid Hemorrhages Animal Model Animals Anticoagulants Antioxidants Astrocytes Biological Models Biology Biomimetics Blast Injuries Blood Blood - brain barrier anatomy Blood Vessels Brain Brain Aneurysms Brain Pathology Cell Communication Cell Culture Techniques Cell Death Cell physiology Cells Cerebral Ischemia Cerebrovascular Disorders Cerebrovascular system Cessation of life Clinical Treatment Clinical Trials Coculture Techniques Complex Data Development Devices Dextrans Drug Kinetics Drug Targeting Endothelial Cells Endothelium Engineering Ensure Equipment Event Extracellular Matrix Extravasation Failure Foundations Future Glucose Goals Growth Hemorrhage Hemorrhagic Disorders Heparin Human Hydrogels In Vitro Incidence Induced pluripotent stem cell derived neurons Inflammation Inflammatory Intervention Ischemia Knowledge Label Life Long-Term Effects Macrophage Managed Care Measures Mentors Microfluidic Microchips Microfluidics Modeling Neuroglia Neurons Optic Nerve Oxygen Pathology Pathway interactions Patients Perfusion Pharmaceutical Preparations Physiological Physiology Polymers Pre-Clinical Model Production Property Quality of life Reactive Oxygen Species Reproducibility Research Research Personnel Running Rupture Stroke Structure Subarachnoid Hemorrhage Sulfides System Techniques Technology Testing Therapeutic Thrombosis Tight Junctions Tissue Engineering Tissues Toxic effect Training Translating Vascularization Vasospasm Work arteriole barrier to testing blood perfusion blood-brain barrier disruption blood-brain barrier function brain tissue cerebrovascular deprivation design drug discovery drug release profile effective therapy experience fabrication functional outcomes fundamental research human model improved improved outcome in vitro Model in vivo in vivo Model induced pluripotent stem cell manufacture nanoparticle nanoparticle delivery neovascularization nervous system disorder neural neuron loss neuroprotection neurovascular neurovascular unit novel novel therapeutics propylene protective efficacy response screening spatiotemporal stroke event stroke-like episode success targeted treatment therapeutic development therapeutic nanoparticles vasogenic edema

项目摘要

Project Summary In this MOSAIC K99/R00 Pathway to Independence application, Dr. Brian O’Grady proposes training in models of subarachnoid hemorrhage (SAH) and development of therapeutics that will strategically compliment his expertise in the development of arteriole-specific growth of ex vivo brain tissue in a biomimetic hydrogel and 3D printed microfluidic fabrication. The training plan is paired with scientific studies that will develop and apply a novel microfluidic device for modeling subarachnoid hemorrhage stroke events and for use as a screening platform for a dual-targeted nanoparticle as a potential therapeutic for the damage caused by SAH and delayed cerebral ischemia. Dr. O’Grady’s primary goal is to become an independent researcher focused on creating biomimetic in vitro models of the brain vasculature and developing novel therapeutics for neurological diseases. The rigorous training described and the outstanding team of mentors in vascular biology (Dr. Lippmann), neurological disease pathology (Dr. Jefferson), and nanoparticle development and therapeutics (Dr. Duvall) will ensure his success in transitioning to independence. Through his training plan, Dr. O’Grady will gain 1) deeper knowledge of blood-brain barrier physiology and the neurovascular unit; 2) experience synthesizing and characterizing nanoparticles; 3) knowledge of modeling SAH and neurological disorders in vitro; and 4) strategies for running a successful interdisciplinary and collaborative research lab. SAH is defined as a cerebrovascular disease with the initial event of a ruptured brain aneurysm and accounts for 5% of all types of strokes. Despite this small percentage, SAH accounts for one third of all stroke-related years of potential life lost before the age of 65. While a new era of neurocritical care management has contributed to improved outcomes for SAH, the secondary consequences result in delayed cerebral ischemia (DCI). DCI has varying degrees of patient functional outcome and has no known interventions to improve quality of life. This lack of effective treatments is largely attributed to the high failure rate of translating brain-targeting drugs from animals to humans. Recently, there has been a global effort to produce a tissue engineered, in vitro model system that can represent the complex vascular anatomy and microenvironment of the neurovascular unit. Dr. O’Grady’s preliminary work demonstrates that a novel biomimetic hydrogel supports induced pluripotent stem cell-derived neural, mural, and glial cells and induces arteriole-specific growth of ex vivo human brain vasculature. This new vasculature consists of anatomically correct, concentric layered structures that were previously unobtainable. When supported by a microfluidic device, the arterioles anastomose and can be lumen- perfused and photoablated. Based on his preliminary data, Dr. O’Grady hypothesizes that the dynamic neurovascular microenvironment of a stroke-like event can be accurately modeled by this new in vitro system. In addition to developing a new in vitro model of SAH, this project will test and validate the neural protective efficacy of a dual-targeted therapeutic for SAH and DCI in the human in vitro model.

项目概要在这份 MOSAIC K99/R00 独立之路申请中，Brian O’Grady 博士建议进行以下方面的培训：蛛网膜下腔出血 (SAH) 模型和战略性补充疗法的开发他在仿生水凝胶中开发离体脑组织小动脉特异性生长方面的专业知识该培训计划与开发和应用 3D 打印微流体制造的科学研究相结合。用于模拟蛛网膜下腔出血中风事件并用作筛查的新型微流体装置双靶点纳米颗粒平台作为 SAH 和延迟性损伤的潜在治疗方法奥格雷迪博士的首要目标是成为一名专注于脑缺血的独立研究员。创建脑血管系统的仿生体外模型并开发治疗小说神经系统疾病方面所描述的严格培训和优秀的导师团队。（李普曼博士）、神经疾病病理学（杰斐逊博士）以及纳米颗粒开发和治疗（杜瓦尔博士）将确保他成功过渡到独立。通过他的培训计划，奥格雷迪博士将确保他成功过渡到独立。获得 1) 更深入的血脑屏障生理学和神经血管单元知识 2) 经验；纳米颗粒的合成和表征；3) SAH 和神经系统疾病建模知识体外；4) 成功运行跨学科和协作研究实验室的策略。 SAH 被定义为一种以脑动脉瘤破裂为首发事件的脑血管疾病及其解释占所有类型中风的 5%，尽管这一比例很小，但 SAH 却占所有中风相关疾病的三分之一。 65 岁之前损失的潜在寿命。虽然神经重症监护管理的新时代做出了贡献为了改善 SAH 的预后，迟发性脑缺血 (DCI) 的继发后果已得到改善。患者的功能结果有不同程度的变化，并且没有已知的干预措施可以改善生活质量。缺乏有效的治疗方法很大程度上归因于从大脑中转化脑靶向药物的失败率很高。最近，全球都在努力生产组织工程体外模型。可以代表神经血管单元的复杂血管解剖结构和微环境的系统。奥格雷迪的初步工作表明，一种新型仿生水凝胶支持诱导多能干细胞衍生的神经细胞、壁细胞和神经胶质细胞，并诱导离体人脑的小动脉特异性生长这种新的脉管系统由解剖学上正确的同心分层结构组成。当微流体装置支持时，小动脉会吻合并且可以是腔内的。奥格雷迪博士根据他的初步数据，证实了这一动态。这种新的体外系统可以准确地模拟中风样事件的神经血管微环境。除了开发新的蛛网膜下腔出血体外模型外，该项目还将测试和验证神经保护作用双靶向疗法在人体体外模型中对 SAH 和 DCI 的疗效。