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iPSC-derived Neurovascular Organoids

iPSC 衍生的神经血管类器官

基本信息

批准号：
10775461
负责人：
Ethan Lippmann
金额：
$ 12.2万
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/10775461
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 Central Nervous System Diseases Cerebral small vessel disease Chronic Complement Coupled Cues Data Development Disease Disease model Drug Evaluation Drug toxicity Drug usage Electrophysiology (science)Endothelial Cells Engineering Epitopes Exhibits Functional disorder Gelatin Genetic Variation Genotype Growth Health Human Human Biology Hydrogels Image In Vitro Induced pluripotent stem cell derived neurons Injury Investigation Methacrylates Microfabrication Microvascular Dysfunction Modeling Molecular N-Cadherin Nerve Degeneration 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 neural circuit neural patterning neurovascular neurovascular injury novel prevent prospective 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.

汇总表