Development of 3D vascularized model of Blood Brain Barrier and its application to Alzheimer disease research

血脑屏障3D血管化模型的开发及其在阿尔茨海默病研究中的应用

• 批准号: 10016386
• 负责人: ROGER D KAMM
• 金额: $ 20.05万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10016386
• 关键词: 3-Dimensional; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyloid deposition; Astrocytes; Biochemical; Biological Assay; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Cell Culture Techniques; Cell Differentiation process; Cell model; Cells; Cerebrovascular Disorders; Chemicals; Clinical Research; Coculture Techniques; Data; Dementia; Deterioration; Development; Disease; Disease Progression; Disseminated Malignant Neoplasm; Drug Targeting; Endothelial Cells; Environment; Exposure to; Extracellular Matrix; Functional disorder; Genes; Human; Human Characteristics; Impaired cognition; In Vitro; Island; Lead; Membrane; Methods; Microfluidics; Modeling; Molecular; Morphology; Mutation; Nervous System Physiology; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Pathogenesis; Pathogenicity; Pathologic; Pericytes; Permeability; Pharmaceutical Preparations; Physiological; Population; Property; Reporting; Research; Research Design; Role; Scientist; Senile Plaques; Signal Transduction; Standardization; System; Tauopathies; Testing; Tight Junctions; Time; Vascular Diseases; Work; abeta deposition; age related; amyloid peptide; base; blood-brain barrier disruption; blood-brain barrier function; brain endothelial cell; cerebral capillary; cognitive function; design; drug discovery; experience; experimental study; extracellular; familial Alzheimer disease; follow-up; fundamental research; human disease; hyperphosphorylated tau; improved; induced pluripotent stem cell; interest; monolayer; nerve stem cell; nervous system disorder; neurovascular unit; novel; novel therapeutics; overexpression; presenilin-1; prevent; protein expression; relating to nervous system; response; scaffold; screening; three dimensional cell culture; tool

SUMMARY As the population grows older, the demand for improved methods to study cerebrovascular diseases has rapidly increased. At the same time, there has been burgeoning interest in reproducing physiological properties of blood- brain-barrier (BBB) in vitro that can be helpful in both basic and clinical studies. A need therefore exists for standardized models as tools to help scientists better understand the physiological and pathological mechanisms involved in cerebrovascular diseases, including Alzheimer’s disease (AD). The proposed studies are aimed at developing a versatile BBB model that recapitulates BBB microvascular networks (µVNs) in a three dimensional (3D) microfluidic platform, and apply this model to AD pathogenesis research. Building on our extensive set of preliminary and related data, we propose to recreate 3D AD-BBB µVNs within extracellular matrix (ECM) scaffolds that enable intercellular signaling and exposure to biochemical gradients in a well-defined microenvironment. AD is a progressive neurodegenerative disease which is characterized by deterioration of cognitive function and deposition of β-amyloid (Aβ) peptides. We previously reported that human neural progenitor cells overexpressing Familial AD (FAD) mutations in the amyloid-β precursor protein (APP) and presenilin 1 (PSEN1) genes grown in a 3D culture system successfully recapitulate AD pathologies (3D AD culture model). However, this model lacks BBB components, which are critical to neurological function and AD pathogenesis. We will develop 3D- differentiated AD cells in a 3D microfluidic platform in the presence of the BBB µVNs (3D AD-BBB µVN model). We will investigate how the BBB is disrupted in AD and whether optimizing the BBB can ameliorate AD progression. Our 3D AD-BBB µVN model will be useful for both BBB-related disease pathogenic cascades, such as AD, and drug discovery in a human brain-like environment.

总结 随着人口老龄化，对研究脑血管疾病的改进方法的需求迅速增加。 增加与此同时，人们对再现血液的生理特性的兴趣也在迅速增长- 体外脑屏障（BBB），这对基础和临床研究都有帮助。因此需要 标准化模型作为工具，帮助科学家更好地了解生理和病理机制 参与脑血管疾病，包括阿尔茨海默病（AD）。拟议的研究旨在 开发一种通用的BBB模型，在三维空间中重现BBB微血管网络（µ VN）， (3D)微流控平台，并将该模型应用于AD发病机制的研究。基于我们广泛的 初步和相关数据，我们建议在细胞外基质（ECM）内重建3D AD-BBB µ VN 支架，使细胞间信号传导和暴露于生化梯度，在一个明确的 微环境 AD是一种进行性神经退行性疾病，其特征在于认知功能恶化， β-淀粉样蛋白（Aβ）肽沉积。我们以前报道过，人类神经祖细胞过度表达， 生长在成年人中的淀粉样β前体蛋白（APP）和早老素1（PSEN 1）基因的家族性AD（FAD）突变 3D培养系统成功地再现了AD病理（3D AD培养模型）。然而，这一模式缺乏 BBB成分，其对神经功能和AD发病机制至关重要。我们将开发3D- 在3D微流体平台中在BBB μ VN的存在下分化的AD细胞（3D AD-BBB μVN模型）。 我们将研究AD中BBB是如何被破坏的，以及优化BBB是否可以改善AD 进展我们的3D AD-BBB µVN模型将用于BBB相关疾病的致病级联，例如 以及在类似人脑的环境中发现药物。