A Vascularized Micro-Organ platform for the study of Brain-BBB-Blood interaction

用于研究脑-血脑屏障-血液相互作用的血管化微器官平台

基本信息

批准号：
10064588
负责人：
CHRISTOPHER C. W. HUGHES
金额：
$ 64.08万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
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/10064588
关键词：
Acids Affect Alzheimer&apos s Disease Amyloid beta-Protein Anastomosis - action Anatomy Animals Arteries Astrocytes Basement membrane Biological Models Blood Blood - brain barrier anatomy Blood Cells Blood Glucose Blood Substitutes Blood Vessels Blood flow Brain CADASIL CAG repeat Cell Communication Cells Communication Barriers Complex Data Development Diagnostic Disease Progression Disease model Endothelial Cells Face Foot Process Gene Expression Genes Genetic Glucose Goals Human Huntington Disease Huntington gene Huntington protein Individual Insulin Light Lipids Membrane Microfluidics Microglia Modeling Movement Multiple Sclerosis Neurodegenerative Disorders Neurons Organ Parkinson Disease Pathogenesis Pathology Pericytes Pharmaceutical Preparations Phase Phenotype Physiological Process Proteins Regulation Role Running Science Signal Transduction Stroke Testing Thalamencephalon Therapeutic Tight Junctions Transferrin Translating Traumatic Brain Injury Veins WNT Signaling Pathway Work base brain cell brain parenchyma cell type cerebral blood volume density drug development foot in vitro Model mutant nervous system disorder neuropathology neurovascular neurovascular unit novel novel therapeutic intervention organ on a chip polyglutamine pressure relating to nervous system response side effect transcytosis

项目摘要

PROJECT SUMMARY For too long, studies of the Blood-Brain Barrier (BBB) have ignored the blood component of this interface, focusing almost exclusively on the cells of the Neurovascular Unit (NVU). The goal of the FOA to which we are responding aims to change this: “The intent of this FOA is to stimulate the development of a new field of blood-based science by re-defining the neurovascular unit as a component of the blood-brain interface. This will facilitate development of human- based neurovascular-blood models to identify targets for diagnostics and regulation of the blood-brain interface…” The NVU is comprised of endothelial cells (EC), pericytes and astrocytes, and a complex basement membrane, which work together to severely limit the free movement of molecules from the blood into the brain parenchyma. In response to local signals during development BBB EC develop tight junctions and have very low rates of transcytosis. The side-effect of this is that access of potentially therapeutic drugs into the brain is also compromised. In this proposal we will build on our well-established human Vascularized Micro-Organ (VMO) platform to create a novel blood-brain interface model, the VMO-B. In this model a network of human microvessels anastomoses to microfluidic channels representing an artery and a vein and are induced to a BBB phenotype by Wnt signaling. The vessels are invested by pericytes and contacted by astrocyte foot-processes. Importantly, we will run a blood substitute – VMOBlood – through the vessels that will mimic the composition of blood, including protein and lipid content. We will then use the VMO-B to investigate the process of BBB breakdown in the pathogenesis of Huntington’s disease. We already have preliminary data suggesting that expression of mutant HTT protein in EC causes BBB deficits. We will investigate crosstalk between blood and the cells of the NVU, and how expression of mHTT in each cell type affects cell-cell communication and barrier function. In the R61 phase we will pursue three aims: Aim 1 Develop a stable MPS BBB model with perfused microvasculature; Aim 2 Incorporate flow of blood into BBB microfluidic model; and, Aim 3 Characterize key transporters at the blood-brain interface. In the R33 phase we will use this platform to examine the role of the blood-brain interface in the pathology of HD through an additional two aims: Aim 4 Test the hypothesis that expression of mHTT in EC disrupts transport across the BBB leading to changes in the neural micro-environment; and, Aim 5 Test the hypothesis that expression of mHTT disrupts multiple cell-to-cell interactions at the blood- brain interface. Completion of this project will not only shed light on the neuropathology of Huntington’s disease, but will also yield a platform ideally suited to drug development and investigating the role of the blood- brain interface in numerous neurological diseases including Alzheimer’s disease, Multiple Sclerosis, Parkinson’s disease, stroke, CADASIL, and traumatic brain injury.

项目概要长期以来，对血脑屏障（BBB）的研究忽略了这个界面的血液成分，几乎完全专注于神经血管单元 (NVU) 的细胞，这是我们 FOA 的目标。响应旨在改变这一点： “该 FOA 的目的是通过重新定义血液科学来刺激血液科学新领域的发展神经血管单元作为血脑界面的一个组成部分，这将促进人类的发展。基于神经血管血液模型来确定血脑诊断和调节的目标界面…” NVU 由内皮细胞 (EC)、周细胞和星形胶质细胞以及复杂的基底膜组成，它们共同作用，严重限制分子从血液到脑实质的自由运动。在发育过程中响应局部信号 BBB EC 形成紧密连接并且具有非常低的比率转胞吞作用的副作用是潜在的治疗药物进入大脑也会受到影响。在这项提案中，我们将建立在我们完善的人体血管微器官（VMO）的基础上。平台创建了一种新颖的血脑接口模型，VMO-B 在该模型中是一个人类网络。微血管与代表动脉和静脉的微流体通道吻合，并被诱导形成血脑屏障血管由周细胞覆盖并由星形胶质细胞足突接触。重要的是，我们将通过模拟血液成分的血管运行一种血液替代品 - VOBlood 然后我们将使用 VMO-B 来研究 BBB 的过程。我们已经有初步数据表明亨廷顿病的发病机制。 EC 中突变 HTT 蛋白的表达会导致 BBB 缺陷，我们将研究血液和血脑屏障之间的串扰。 NVU 的细胞，以及 mHTT 在每种细胞类型中的表达如何影响细胞间通讯和屏障在 R61 阶段，我们将追求三个目标：目标 1 开发稳定的灌注 MPS BBB 模型。目标 2 将血流纳入 BBB 微流体模型；目标 3 表征关键在 R33 阶段，我们将使用该平台来检查血脑界面转运蛋白的作用。 HD 病理学中的血脑界面还通过另外两个目标：目标 4 检验以下假设： EC 中 mHTT 的表达会扰乱跨 BBB 的运输，导致神经微环境发生变化；目标 5 检验 mHTT 的表达破坏血液中多种细胞间相互作用的假设该项目的完成不仅将揭示亨廷顿舞蹈症的神经病理学。疾病，但也将产生一个非常适合药物开发和研究血液作用的平台多种神经系统疾病的大脑接口，包括阿尔茨海默病、多发性硬化症、帕金森病疾病、中风、CADASIL 和创伤性脑损伤。