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) 是第六大死因，但目前仍没有发现这种疾病。 市场上可减缓或阻止 AD 神经元损伤的药物治疗。 是散发性 AD 的最强遗传风险因素，大约四分之一的人群患有此病 重要的是，缺乏基于人体的模型进一步阻碍了有效的治疗开发。 可以用免疫-胶质-神经血管单元中所有大脑驻留细胞类型来概括 AD 病理学， 图解关键细胞非自主效应，包括炎症和脂质失调以及血脑 屏障（BBB）介导的营养物和疗法的运输为了解决这些局限性，我们雄心勃勃。 在我博士后工作的第一阶段的登月项目中，我设计了一种新颖的拟脑矩阵 (NeuroMatrix) 支持来自患者特异性诱导多能干细胞的所有 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集成大脑模型（miBRAIN）。 APOE4 相关失调和神经元过度兴奋、淀粉样蛋白积累的 AD 病理特征 此外，我还开发了一种新颖的收缩最小化微流体 我建议在 NeuroMatrix 中实现神经血管单元内可灌注脉管系统的装置。 目标：（目标 1）利用 miBRAIN 平台构建跨领域的多元化“体外患者队列” APOE 基因型与等基因系可探测 APOE4 特异性效应并进行重要验证 该模型，因为我的目标是磨练该平台技术以实现广泛的实用性和（目标 2）工程师 3D-miBRAIN- 将我的新型微流体装置与 miBRAIN 相结合并成功集成每种细胞类型的芯片 miBRAIN 培养物中完全可灌注的 BBB，并利用它们对 BBB 渗透进行功能评估 与项目官员协商后，确定患者细胞系的能力和选择性以及 APOE 状态。 鉴于我的长期目标，我决定进一步关注（目标 3）调查最佳前进道路 用于部署该技术以实现最大效用，包括制定业务计划和识别 因此，这项工作可能会给 AD 机制带来重要的见解。 了解与 APOE4 风险相关的其他神经退行性疾病直接相关，同时 开发经过充分验证的 3D-miBRAIN-Chip 平台技术，该技术是一种集成的免疫-胶质-神经血管- 具有患者特异性遗传学和仿生表型和功能的细胞单元，对于 同时，它还提供了重要的研究方法培训。 ods（平台开发、生物信息学、脂质组学和炎症分析、专家联合指导 导师和科学咨询委员会）和职业发展（沉浸式创业培训， 针对特定领域的课程、专家共同导师和创业咨询委员会的指导、追求 雄心勃勃的独立愿景），这将对我的独立职业生涯产生显着影响。