A Neurovascular Microphysiological System

神经血管微生理系统

• 批准号: 10226823
• 负责人: WILLIAM L. MURPHY
• 金额: $ 34.02万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 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/10226823
• 关键词: 3-Dimensional; Alexander Disease; Alzheimer' 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

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.

项目总结/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1980年代的2000人中有1人增加到最近报告的2000人中有1人。 据CDC报道，68人中有1人。此外，由于寨卡病毒暴露导致的原发性小头畸形病例 引起了全球的关注，由沙利度胺和产前酒精暴露引起的出生缺陷突出了 重要的是开发合适的模型系统，以了解，检测和治疗这些疾病的原因。 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， 因为重点是神经和神经胶质细胞类型的作用。然而，一些神经发育和 神经变性疾病与血管畸形，包括小头畸形， 脑海绵状畸形、自闭症、阿尔茨海默病、亚历山大病和雷特综合征。的 发育中的大脑在神经发育的早期阶段最脆弱， 脆弱性是发育中的大脑从相关的神经周围血管丛开始的初始血管化 （PNVP），其中血脑屏障尚未完全形成。到目前为止，还没有一个人类模型可以模仿 脑血管系统的情况我们建议产生一个神经血管微生理系统（NV- MPS），其模拟发育中的大脑的初始血管化，并使模型进展以支持长的血管化。 长期维持一个工程化的可再生脑类器官。建议的研究将实现三个具体目标 目标。Specific Aim 1将使用无管脑微生理系统（MPS）创建一个发育中的脑微生理系统。 微流体装置、合成水凝胶和人PSC衍生的细胞类型。Specific Aim 2将生成模型 并测量分子、细胞和组织水平的输出， 是神经周围血管丛形成、神经血管整合和随后的皮质 成熟具体目标3将测量和刺激NV-MPS中的神经元电生理功能 使用集成的细胞报告器和光学透明的嵌入式电极。完成这项研究 将提供一种简单、稳健和可靠的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 在神经发育的早期阶段暴露于外源性物质，最终将创造一个可灌注的血管系统， 喂养和维持工程神经类器官。