iPSC-derived Neurovascular Organoids

iPSC 衍生的神经血管类器官

基本信息

批准号：
10683029
负责人：
Ethan Lippmann
金额：
$ 10.85万
依托单位：
VANDERBILT UNIVERSITY
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：
2020-04-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10683029
关键词：
3-Dimensional Academic Medical Centers Acute Alzheimer&apos s Disease Alzheimer&apos s disease risk Animal Model Animals Architecture Biocompatible Materials Biological Assay Biological Models Biomimetics Blood - brain barrier anatomy Blood Vessels Blood capillaries Brain Brain region Cell Culture Techniques Cell Line Cells Central Nervous System Diseases Cerebral small vessel disease Chronic Complement Coupled Cues Data Dementia Development Disease Disease model Drug Evaluation Drug toxicity Drug usage Electrophysiology (science)Endothelial Cells Engineering Epitopes Exhibits Functional disorder Gel Gelatin Genetic Variation Genotype Growth Health Human Human Biology Hydrogels Image Impaired cognition In Vitro Induced pluripotent stem cell derived neurons Injury Investigation Methacrylates Microfabrication Microvascular Dysfunction Modeling Molecular N-Cadherin Nerve Degeneration Neuraxis Neurodegenerative Disorders Neuroglia Neurologic Neurons Organoids Outcome Measure Pattern Peptides Pericytes Physiological Polymers Prosencephalon Radial Reperfusion Injury Resources Signal Transduction Slice Structure Synapses System Techniques Technology Therapeutic Time Tissue constructs Tissues Toxicology Universities Variant Vascularization Work angiogenesis blood damage blood-brain barrier disruption blood-brain barrier function brain endothelial cell density disease mechanisms study disease phenotype drug discovery drug efficacy functional outcomes genetic risk factor human disease hydrogel scaffold improved in vitro Model in vivo in vivo Model induced pluripotent stem cell induced pluripotent stem cell technology mimetics mouse model neural circuit neural patterning neurovascular neurovascular injury novel prevent prospective relating to nervous system response stem cell differentiation two-dimensional vascular cognitive impairment and dementia vascular contributions

项目摘要

Summary statement Robust model systems are essential for understanding human disease. While Alzheimer’s disease can be studied using in vivo models that have become more representative in recent years (e.g. by introducing natural genetic diversity and humanized APOE variants into existing Alzheimer’s mouse models), the ability to study vascular contributions to cognitive impairment and dementia (VCID) and cerebral small vessel disease (SVD) remains difficult. Indeed, the molecular mechanisms underlying VCID and SVD remain mostly unknown, and in vivo models for these diseases are lacking. A representative human in vitro model would therefore be beneficial to complement in vivo systems and improve understanding of vascular contributions to neurodegeneration. The development of human induced pluripotent stem cell (iPSC) technology has increased the utility of in vitro central nervous system (CNS) models, which have gradually progressed from isolated two-dimensional cell cultures to multi-cellular three-dimensional assemblies that better recapitulate the organization and architecture of specific brain regions. However, these human ‘brain organoids’ still have significant deficits. Notably, cortical organoids exhibit improperly organized laminar architectures and lack perfusable microvasculature with blood-brain barrier (BBB) function. These deficits limit the representativeness of using brain organoids to understand the mechanisms of VCID and SVD. In this proposed project, we will develop a biomimetic brain organoid platform with robust neurovascular function. Aim 1 of this proposal will characterize the organization and maturation of cortica. organoids grown in a novel biomaterial that mimics cues provided by radial glia to help guide laminar patterning. Aim 2 will focus on integrating brain endothelial cells and pericytes with the cortical organoids to develop perfusable microvasculature throughout the tissue construct, thereby generating the ‘neurovascular organoid’ platform. Aim 3 will then validate the representativeness of the neurovascular organoids by subjecting them to acute and chronic injuries known to damage the BBB; in particular, iPSCs with defined APOE genotype will be used to assess onset and progression of neurovascular dysfunction in response to this well-established genetic risk factor. Overall, this project will establish a human in vitro model of the vascularized cortex that is expected to have utility for unraveling the mechanisms of VCID and SVD.

摘要声明强大的模型系统对于理解人类疾病至关重要。虽然可以使用近年来变得更具代表性的体内模型来研究阿尔茨海默氏病（例如，通过将自然遗传多样性和人源化APOE引入现有阿尔茨海默氏症的老鼠模型），但研究认知障碍和痴呆症（VCID）和Cerebral小型疾病（SV）的血管贡献的能力仍然很困难。实际上，VCID和SVD的分子机制仍然主要未知，并且缺乏这些疾病的体内模型。因此，代表性的人体体外模型将有益于在体内系统的完成并提高对神经变性的血管贡献的理解。人类诱导的多能干细胞（IPSC）技术的开发增加了体外中枢神经系统（CNS）模型的实用性，这些模型已逐渐从孤立的二维细胞培养物到多细胞三维组件，以更好地重新培养特定大脑区域的组织和建筑。但是，这些人类的“脑器官”仍然存在明显的缺陷。值得注意的是，皮质器官表现出不当组织的层状结构，并且缺乏具有血脑屏障（BBB）功能的垂体微脉管系统。这些定义限制了使用脑器官了解VCID和SVD的机制的代表性。在这个拟议的项目中，我们将开发具有强大神经血管功能的仿生脑器官平台。该提案的目标1将表征Cortica的组织和成熟。在一种新型的生物材料中生长的类器官，该材料模仿了Radial Glia提供的提示，以帮助指导层状图案。 AIM 2将专注于将脑内皮细胞和周细胞与皮质器官整合在一起，以在整个组织构建体中形成可灌注的微脉管系统，从而产生“神经血管器官”平台。然后，AIM 3将通过使神经血管器官遭受急性和慢性损伤损害BBB来验证神经血管器官的代表性；特别是，具有定义的APOE基因型的IPSC将用于评估对这种良好的遗传危险因素的响应神经血管功能障碍的发作和进展。总体而言，该项目将建立一个人类的体外模型的血管化皮质模型，该模型有望具有揭示VCID和SVD机制的实用性。