Engineering Immuno-Glial-Neurovascular 3D-Brain-Chips with a Perfusable BBB for Accelerating Alzheimer’s Disease Drug Discovery and Translation

工程免疫胶质神经血管 3D 脑芯片与可灌注 BBB 加速阿尔茨海默病药物发现和转化

• 批准号: 10741377
• 负责人: Alice Stanton
• 金额: $ 16.39万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10741377
• 关键词: 3-Dimensional; Acceleration; Address; Advisory Committees; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloid; Back; Biocompatible Materials; Bioinformatics; Biomimetics; Blood - brain barrier anatomy; Blood Tests; Brain; Businesses; Cause of Death; Cell Line; Cells; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Coculture Techniques; Consultations; Custom; Data; Development; Engineering; Feedback; General Population; Genetic; Genotype; Goals; Human; Immune; In Vitro; Inflammation; Inflammatory; Interview; Lipids; Longitudinal cohort; Marketing; Mediating; Mentors; Microfluidic Microchips; Modeling; Neurodegenerative Disorders; Neurologic Effect; Neurons; Nutrient; Pathogenesis; Pathologic; Pathology; Patients; Permeability; Pharmacological Treatment; Phase; Phenotype; Physiological; Positioning Attribute; Postdoctoral Fellow; Property; Race; Reproducibility; Research Methodology; Resources; Risk; Stratification; Stream; Structure; Technology; Testing; Therapeutic; Tissue Model; Training; Translating; Translations; Transport Process; Validation; Vision; Work; apolipoprotein E-3; apolipoprotein E-4; blood-brain barrier permeabilization; brain cell; brain tissue; career; career development; cell type; cohort; constriction; cost; drug development; drug discovery; genetic risk factor; improved; in vivo; induced pluripotent stem cell; insight; invention; lipidomics; mimetics; neurovascular; neurovascular unit; novel; patient population; patient stratification; predictive modeling; programs; response; screening; self assembly; sex; tau-1; technology platform; therapeutic development; therapeutically effective; tool

PROJECT SUMMARY. While Alzheimer’s Disease (AD) is the sixth leading cause of death, there is still no pharmacologic treatment on the market that slows or stops neuronal damage in AD. Apolipoprotein-E4 (APOE4) is the strongest genetic risk factor for sporadic AD and one that roughly a quarter of the general population carries. Importantly, further precluding effective therapeutic development is the lack of human-based models that can recapitulate AD pathology with all the brain-resident cell types in the immune-glial-neurovascular unit, cap- turing critical cell non-autonomous effects, including in inflammatory and lipid dysregulation, and blood brain barrier (BBB)-mediated transport of nutrients and therapeutics. To address these limitations, in an ambitious moonshot project in the first phase of my postdoctoral work, I have engineered a novel brain-mimetic matrix (NeuroMatrix) that supports the co-culture of all 7 brain cell types from patient-specific induced pluripotent stem cells with mature phenotypes to form a multi-cellular integrated brain model (miBRAIN). This model recapitulates APOE4-associated dysregulation and AD pathological hallmarks of neuronal hyperexcitability, amyloid accumu- lation, phosphorylated tau burden, etc. Further, I have developed a novel constriction-minimizing microfluidic device that enables perfusable vasculature within neurovascular units self-assembled in NeuroMatrix. I propose here to: (Aim 1) leverage the miBRAIN platform to construct a diverse “in vitro patient cohort” across APOE genotype with isogenic lines to probe APOE4-specific effects and conduct important validation of the model as I aim to hone this platform technology for broad utility and (Aim 2) engineer 3D-miBRAIN- Chips by combining my novel microfluidic devices with the miBRAIN and successively integrating each cell type towards a fully perfusable BBB within miBRAIN culture and harness them to functionally assess BBB perme- ability and selectivity across patient cell lines and APOE status. After consultation with the Program Officer and given my long-term goals, I have decided to further focus on (Aim 3) investigating the best path forward for deploying this technology for maximal utility, including development of a business plan and identification of potential partners and focus applications. This work thus could result in important insights for AD mechanistic understanding, of immediate relevance to other neurodegenerative diseases associated with APOE4 risk, while developing a well-validated 3D-miBRAIN-Chip platform technology that is an integrated immune-glial-neurovas- cular unit with patient-specific genetics and biomimetic phenotypes and functions that could be of great utility for therapeutic development across CNS pathologies. Simultaneously, it provides vital training in research meth- ods (platform development, bioinformatics, lipidomic and inflammation analyses, mentoring from expert Co- Mentors and Scientific Advisory Committee) and career development (immersive entrepreneurial training, niche-specific coursework, mentoring from expert Co-Mentors and Entrepreneurial Advisory Committee, pursuit of ambitious independent vision) that will make a marked difference in launching my independent career.

项目摘要。虽然阿尔茨海默氏病（AD）是第六大死亡原因，但仍然没有 市场上的药理学治疗会减慢或阻止AD中的神经元损害。载脂蛋白-E4（APOE4） 是零星广告的强大遗传危险因素，大约是四分之一的一般人群 携带。重要的是，进一步排除有效的治疗发展是缺乏基于人类的模型 可以用免疫 - 神经血管单元中的所有脑居民细胞类型概括AD病理 图灵关键细胞非自主效应，包括炎症和脂质失调以及血脑 障碍物（BBB）介导的营养和治疗的运输。解决这些限制，以雄心勃勃 在博士后工作的第一阶段，我已经设计了一个新颖的脑模拟矩阵 （Neuromatrix）支持患者特异性诱导的多能茎的所有7种脑细胞类型的共培养 具有成熟表型的细胞形成多细胞整合大脑模型（mibrain）。该模型概括了 APOE4相关的失调和神经元过度兴奋性，淀粉样蛋白累积的AD病理标志 外层，磷酸化的tau burnen等。此外，我开发了一种新颖的收缩最小化微流体 在神经血管单元内自组装中的神经血管单元内的脉动脉管系统的设备。我建议 在此处：（目标1）利用mibrain平台在整个跨越构建多样的“体外患者队列” 具有同源线的APOE基因型，可探测APOE4特异性效应并进行重要验证 我的目标是磨练该平台技术用于广泛实用程序，并且（AIM 2）工程师3D-Mibrain- 通过将我的新型微流体设备与mibrain结合并成功整合每种单元格的芯片 在mibrain培养物中完全灌注BBB，并利用它们在功能上评估BBB渗透 患者细胞系和APOE状态的能力和选择性。在与计划官员协商后 鉴于我的长期目标，我决定进一步专注于（目标3）调查前进的最佳途径 用于部署这项技术以最大程度的效用，包括制定业务计划和身份证 潜在的合作伙伴和专注应用程序。因此，这项工作可能会导致广告机械的重要见解 了解与APOE4风险相关的其他神经退行性疾病的直接相关性，而 开发验证良好的3D-MIBRAIN-CHIP平台技术，该技术是一种综合的免疫 - 胶质神经洛瓦斯 - 具有特异性遗传学和仿生表型和功能的克拉里单元，可能是非常有用的 CNS病理学的治疗性发育。同时，它在研究中提供了重要的培训 - ODS（平台开发，生物信息学，脂质组和注射分析，专家共同的心理 导师和科学咨询委员会）和职业发展（沉浸式企业家培训， 特定于利基的课程，专家联合会和企业家咨询委员会的心理，追求 雄心勃勃的独立愿景）将在启动我的独立职业方面显着差异。