A Neurovascular Microphysiological System

神经血管微生理系统

基本信息

批准号：
9925300
负责人：
WILLIAM L. MURPHY
金额：
$ 33.91万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9925300
关键词：
3-Dimensional Alexander Disease Alzheimer&apos s Disease Architecture Attention Autopsy Biological Biological Models Biological Process Biology Blood - brain barrier anatomy Blood Vessels Brain Brain Diseases Calcium Cell Line Cell physiology Cells Centers for Disease Control and Prevention (U.S.)Cerebrovascular system Child Congenital Abnormality Cultured Cells Dengue Virus Development Devices Disease Disease model Electrodes Electrophysiology (science)Embryo Endothelial Cells Engineering Etiology Event Feeds Fetal Alcohol Exposure Goals Human Hydrogels Incidence Individual Maintenance Measurable Measures Metabolic Microcephaly Microfluidic Microchips Microfluidics Microglia Modeling Molecular Neurodegenerative Disorders Neurodevelopmental Disorder Neuroglia Neurons Optics Organoids Outcome Output Pathology Patients Pericytes Phenotype Reporter Reporting Reproducibility Research Rett Syndrome Rodent Model Role Route Synaptic Potentials Teratogens Testing Thalidomide Tissues Transgenic Mice Vascularization Work Xenobiotics Zika Virus angiogenesis autism spectrum disorder brain research cell type cerebral cavernous malformations engineered stem cells human model human pluripotent stem cell immunocytochemistry in vivo induced pluripotent stem cell innovation malformation microfluidic technology microphysiology system mouse model nervous system disorder neurodevelopment neurogenesis neuroimaging neurovascular neurovascular unit perineural relating to nervous system response transcriptome sequencing vascular contributions vasculogenesis

项目摘要

PROJECT SUMMARY/ABSTRACT There has recently been a dramatic increase in incidences of neurodevelopment disorders (NDDs) in children. For instance, autism spectrum disorders have increased from 1 in 2000 people in 1980s to the recently reported 1 in 68 as reported by the CDC. In addition, instances of primary microcephaly due to Zika virus exposure have gained global attention, and birth defects caused by thalidomide and prenatal alcohol exposures highlight the importance of developing suitable model systems to understand, detect, and treat causes of these disorders. The importance of vascular tissue development and its contributions to disease pathologies are often overlooked, as the focus is instead on the role of neural and glial cell types. However, a number of neurodevelopmental and neurodegenerative disorders are directly associated with vascular malformations, including microcephaly, cerebral cavernous malformations, autism, Alzheimer’s disease, Alexander’s disease, and Rett syndrome. The developing brain is at its most vulnerable during the early stages of neurodevelopment, and one key point of vulnerability is the initial vascularization of the developing brain from the associated perineural vascular plexus (PNVP), where the blood brain barrier has yet to fully form. There is to date no human model that mimics the brain vasculature at this critical stage. We propose to generate a neurovascular microphysiological system (NV- MPS) that mimics the initial vascularization of the developing brain and to progress the model to support the long term maintenance of an engineered reproducible brain organoid. The proposed studies will achieve three specific aims. Specific Aim 1 will create a developing brain microphysiological system (MPS) using a tubeless microfluidics device, synthetic hydrogels and human PSC-derived cell types. Specific Aim 2 will generate models of a diseased developing brain and measure molecular, cellular and tissue level outputs that have been identified to be indicators of perineural vascular plexus formation, neurovascular integration and subsequent cortical maturation. Specific Aim 3 will measure and stimulate neuronal electrophysiological function in the NV-MPSs using integrated cellular reporters and optically transparent embedded electrodes. Completion of this research will provide a simple, robust and reliable NV-MPS that will provide the means to study the initial vascularization of the developing brain, the neurovascular contributions to neurological disorders and a means to test the effect of xenobiotic exposures at the early stages of neural development and finally will create a perfusable vasculature that feeds and maintains engineered neural organoids.

项目概要/摘要最近，儿童神经发育障碍（NDD）的发病率急剧增加。例如，自闭症谱系障碍从 2000 世纪 80 年代的 2000 人中就有 1 人增加到最近报道的据 CDC 报告，每 68 例中就有 1 例因接触寨卡病毒而出现原发性小头畸形。引起了全球关注，沙利度胺和产前酒精暴露导致的出生缺陷凸显了开发合适的模型系统来理解、检测和治疗这些疾病的原因非常重要。血管组织发育的重要性及其对疾病病理学的贡献常常被忽视，因为重点是神经细胞和神经胶质细胞类型的作用。然而，许多神经发育和神经胶质细胞类型的作用。神经退行性疾病与血管畸形直接相关，包括小头畸形、脑海绵状血管瘤、自闭症、阿尔茨海默病、亚历山大病和雷特综合征。发育中的大脑在神经发育的早期阶段是最脆弱的，这是神经发育的一个关键点脆弱性是发育中的大脑从相关神经周围血管丛的初始血管化（PNVP），血脑屏障尚未完全形成，迄今为止还没有模仿的人体模型。我们建议建立一个神经血管微生理系统（NV-）。 MPS）模仿发育中的大脑的初始血管化并改进模型以支持长期工程可复制大脑类器官的长期维护拟议的研究将实现三个具体目标。具体目标 1 将使用无内胎创建发育中的大脑微生理系统 (MPS)。微流体装置、合成水凝胶和人类 PSC 衍生细胞类型将生成模型。发育中的患病大脑并测量已确定的分子、细胞和组织水平输出作为神经周围血管丛形成、神经血管整合和随后皮质形成的指标具体目标 3 将测量和刺激 NV-MPS 中的神经元电生理功能。使用集成细胞受体和光学透明嵌入式电极完成这项研究。将提供简单、稳健且可靠的 NV-MPS，为研究初始血管化提供方法发育中的大脑、神经血管对神经系统疾病的贡献以及测试效果的方法神经发育早期阶段的异生素暴露，最终将形成可灌注的脉管系统喂养和维持工程神经类器官。