3D Models of the Blood-Brain Barrier for Studying Trauma-Induced Cerebral and Systemic Injuries

用于研究创伤引起的脑损伤和全身损伤的血脑屏障 3D 模型

基本信息

批准号：
10063457
负责人：
Jing-Fei Dong
金额：
$ 80.68万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-03 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10063457
关键词：
3-Dimensional Acute Affect Aging Alzheimer&apos s Disease Architecture Astrocytes Biochemical Biological Assay Biological Models Biology Biomechanics Blood Blood - brain barrier anatomy Blood Circulation Blood Coagulation Disorders Blood Vessels Blood flow Brain Brain Injuries Cause of Death Cell Communication Cells Cerebral hemisphere hemorrhage Cerebrovascular system Cerebrum Chronic Clinical Complex Critical Pathways Cytoskeleton Development Devices Disease Edema Electron Microscopy Endothelial Cells Engineering Extracellular Fluid Future Heart Hematology Hemostatic function Homeostasis Human ImProv In Vitro Inflammation Inflammatory Injury Intracranial Hemorrhages Intracranial Hypertension Leukocytes Lung Mediating Microglia Modeling Neuraxis Organ Outcome Patients Pattern Pericytes Permeability Phase Phosphotransferases Physiological Plasma Prognostic Marker Regression Analysis Reporting Rest Role Sampling Secondary to Severities Signal Pathway Signal Transduction Site Stroke Structure Study models System Systems Biology TBI Patients Technology Tissues Trauma Traumatic Brain Injury Venous biomarker development blood-brain barrier disruption blood-brain barrier function brain parenchyma cell injury cerebral microvasculature defined contribution diagnostic biomarker disability extracellular vesicles in vivo injured insight kinase inhibitor light microscopy monolayer mouse model nervous system disorder neurovascular neurovascular unit new therapeutic target repaired response shear stress success therapeutic development therapeutic target three-dimensional modeling young adult

项目摘要

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide, affecting young adults and increasingly aging patients. Patients with TBI suffer two distinct but closely related injuries. The primary injury is caused by physical forces that disrupt the structural integrity of the brain and vasculature at the site of impact, whereas the secondary injury is ischemic and inflammatory that disseminates to the most parts of the brain and other organs such as the lungs and the heart. The transition from the primary to the secondary injury is mediated through the blood brain barrier (BBB). BBB is a highly selective semipermeable barrier of microvasculature that separates the circulating blood from the brain parenchyma and extracellular fluid in the central nervous system. It consists of not only endothelial cells and the subendothelial matrix but also other perivascular cells, i.e. peri- cytes and astrocytes, that together form the neurovascular unit. Disrupting BBB at the site of injury permits direct exchange between blood and cerebral components, leading to intracerebral and intracranial hemorrhage, and systemic inflammation and coagulopathy. Despite extensive efforts on TBI-induced cerebral and systemic inju- ries in the past, how local TBI disseminates the secondary injury remains poorly understood, largely due to the lack of a physiologically relevant 3D-model system. In this proposal, we have assembled an interdisciplinary team with expertise in microvascular engineering and vascular biology, hematology and hemostasis, TBI, and cell signaling to reconstruct human BBB. This in vitro reconstructed BBB will 1) be 3D in its microvascular archi- tect to contain cellular and matrix components of BBB, 2) allow for dynamic flow of blood or its components with defined patterns and shear stresses found in arterial and venous blood flow, and 3) permit manipulation at bio- chemical (intracellular signaling) and cellular levels (light and electron microscopy). We will use this model sys- tem to exploit roles of blood derived factors in maintaining and disrupting the BBB integrity and function, to identify intracellular signal pathways (the kinase inhibitor regression analysis) that contribute to BBB breakdown and its repairs using a systems biology approach, and to develop in field or bedside devices that evaluate the state of BBB integrity (new biomarker development) and help developing new therapeutic targets for TBI. Find- ings from this proposed study will have numerous implications in future neurovascular engineering approaches and therapeutic development.

创伤性脑损伤 (TBI) 是全世界死亡和残疾的主要原因，影响年轻人和成年人患者日益老龄化。 TBI 患者遭受两种不同但密切相关的伤害。主要伤害是由破坏撞击部位大脑和脉管系统结构完整性的物理力量引起，而继发性损伤是缺血性和炎症性的，会扩散到大脑的大部分部位，其他器官，如肺和心脏。从原发性损伤到继发性损伤的转变是介导的通过血脑屏障（BBB）。 BBB 是一种高度选择性的微血管半透屏障，将循环血液与中枢神经系统中的脑实质和细胞外液分开。它不仅由内皮细胞和内皮下基质组成，还由其他血管周围细胞组成，即血管周围细胞。细胞和星形胶质细胞共同形成神经血管单元。破坏受伤部位的 BBB 允许直接血液和脑成分之间的交换，导致脑内和颅内出血，以及全身炎症和凝血障碍。尽管针对 TBI 引起的脑部和全身损伤做出了广泛的努力，在过去的研究中，局部 TBI 如何传播继发性损伤仍然知之甚少，这主要是由于缺乏生理相关的 3D 模型系统。在这个提案中，我们汇集了一个跨学科的团队拥有微血管工程和血管生物学、血液学和止血、TBI 等方面的专业知识细胞信号传导重建人类血脑屏障。这种体外重建的 BBB 将 1) 其微血管架构是 3D 的包含 BBB 的细胞和基质成分，2) 允许血液或其成分动态流动动脉和静脉血流中发现的定义模式和剪切应力，3）允许在生物化学（细胞内信号传导）和细胞水平（光学和电子显微镜）。我们将使用这个模型系统研究人员利用血液衍生因子在维持和破坏 BBB 完整性和功能中的作用，识别导致 BBB 破坏的细胞内信号通路（激酶抑制剂回归分析）及其使用系统生物学方法的修复，并在现场或床边设备中开发评估 BBB 完整性状态（新生物标志物开发）并帮助开发 TBI 新治疗靶点。寻找- 这项拟议研究的结果将对未来的神经血管工程方法产生许多影响和治疗的发展。