Construction of an integrated immune - vascular brain - chip as a platform for the study, drug screening, and treatments of Alzheimer's disease

构建集成免疫血管脑芯片作为阿尔茨海默病研究、药物筛选和治疗的平台

• 批准号: 9894186
• 负责人: Joel William Blanchard
• 金额: $ 225.9万
• 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: 2019-09-20 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9894186
• 关键词: 3-Dimensional; Affect; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid deposition; Anatomy; Astrocytes; Autopsy; Biochemical; Biopolymers; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Diseases; Calcium; Cell Line; Cells; Cerebral Amyloid Angiopathy; Cerebrovascular Disorders; Clinic; Clinical; Clinical Research; Coculture Techniques; Communities; Complex; Computer Simulation; Coupled; Data; Deposition; Depressed mood; Development; Disease; Dissection; Drug Screening; Drug toxicity; Drug usage; Engineering; Exhibits; Female; Financial cost; Functional disorder; Funding; Gene Expression Profile; Genetic; Genetic Models; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Risk; Genetic Transcription; Genetic Variation; Genetic study; Genomics; Grant; Heterogeneity; Histologic; Histology; Human; Image; Immune; In Vitro; Individual; Lead; Libraries; Light; Maps; Mediating; Microglia; Modeling; Molecular; Monitor; Neurodegenerative Disorders; Neurons; Oligodendroglia; Organ; Pathogenesis; Pathologic; Pathology; Patients; Pericytes; Pharmaceutical Preparations; Pharmacology; Phase; Physiological; Physiology; Predisposition; Property; RNA; Recording of previous events; Reporter; Resources; Risk; Sampling; Severities; Signal Pathway; Tauopathies; Technology; Therapeutic; TimeLine; Tissue Engineering; Tissues; Toxic effect; Translations; Treatment Efficacy; Variant; brain dysfunction; brain endothelial cell; brain tissue; cell type; cerebrovascular; cerebrovascular pathology; clinical biomarkers; cohort; drug development; drug discovery; genetic risk factor; human disease; human model; human tissue; in vitro Model; in vivo; induced pluripotent stem cell; insight; male; multimodality; non-invasive imaging; novel; novel strategies; novel therapeutics; oligodendrocyte precursor; optogenetics; organ on a chip; pre-clinical; precursor cell; research and development; response; scaffold; screening; single-cell RNA sequencing; stem cell biology; stem cell technology; success; tau Proteins; tool; transcriptomics; treatment response; two-photon; voltage

Abstract Alzheimer's disease (AD) is a debilitating brain disorder, with staggering human and financial cost. While genetic studies are increasingly identifying polymorphisms that correlate with AD, there still is no clear picture of the molecular and cellular players and the extent to which each contributes to AD. The genetic and molecular complexity of AD and the lack of technology for experimentally unraveling it in human tissues create a bottleneck constricting the discovery of therapeutics and their successful translation into the clinic. Using human iPSCs we recently developed an in vitro blood-brain barrier (iBBB) and deployed it to discover mechanisms causing genetic predisposition to cerebral amyloid angiopathy (CAA). Identical to clinical studies, we found that APOE4, the strongest genetic risk factor for CAA and AD significantly increased amyloid deposition in our iBBB. The tractability of our engineered tissues then enabled dissection of the cellular causes of the disease. We found expression of APOE4 in pericytes alone was sufficient to increase cerebral vascular amyloid accumulation. Pinpointing the causal cells mediating CAA risk then enabled molecular and biochemical studies that established the underlying mechanism and revealed new therapeutic opportunities for mitigating genetic risk of CAA and potentially AD. Here, we will build upon our success, using the iBBB as a scaffold; we will incorporate neurons, oligodendrocytes, and microglia to generate a micro-integrated brain on a chip (miBrain-chip). In UG3 Aim1.1 we will establish miBrain-chips that represent healthy and diseased states of the human brain through iterative rounds of optimization that incorporate state-of-the-art biopolymers and engineering expertise from Robert Langer's lab at MIT. UG3 Aim1.2 will integrate and validate genetically encoded modulators and reporters of neuronal activity enabling the miBrain-chip to investigate how neuronal activity is influenced, and in turn, influences AD pathogenesis. UG3 Aim2 will model the pathological progression of AD in miBrain-chips across cohort of male and female sAD iPSC lines for which we have matched brains samples, clinical history, and genomic sequences. We will build computational models describing the transcriptional, cellular-dynamics and histological transformations that lead up to the end-states of post-mortem AD brains. These longitudinal pathological maps from genetically diverse healthy and sAD individuals will yield mechanistic insight into AD development and create a platform for discovery and efficacy screening of therapeutics. We hypothesize that the mechanisms underlying AD are significantly influenced by genetic variability. In UH3 we will establish the mechanisms underlying APOE4 pathogenesis (UH3 Aim1) and then ascertain the efficacy, toxicity, and therapeutic window of a panel of preclinical and clinical AD drugs using isogenic APOE3 and APOE4 miBrain-chips (UH3 Aim2). Our multimodal strategy will shed light on how genetic variation influences AD pathogenesis and therapeutic response, opening up new avenues for expeditious drug discovery and translation of effective therapeutics to the clinic.

抽象的 阿尔茨海默病（AD）是一种使人衰弱的大脑疾病，会造成巨大的人力和经济损失。尽管 遗传学研究越来越多地发现与 AD 相关的多态性，但仍然没有明确的图片 分子和细胞因素的影响以及每种因素对 AD 的影响程度。遗传和 AD 的分子复杂性以及缺乏在人体组织中通过实验阐明其的技术导致 限制治疗方法的发现及其成功转化为临床的瓶颈。使用 我们最近开发了一种体外血脑屏障 (iBBB) 并利用它来发现人类 iPSC 导致脑淀粉样血管病（CAA）遗传易感性的机制。与临床研究相同， 我们发现 APOE4（CAA 和 AD 的最强遗传风险因素）显着增加了淀粉样蛋白 沉积在我们的 iBBB 中。我们的工程组织的易处理性使得我们能够剖析细胞原因 的疾病。我们发现仅周细胞中 APOE4 的表达就足以增加脑血管 淀粉样蛋白积累。查明介导 CAA 风险的致病细胞，然后启用分子和 生化研究确立了潜在机制并揭示了新的治疗机会 降低 CAA 和潜在 AD 的遗传风险。在这里，我们将利用 iBBB 作为我们的成功基础 脚手架;我们将整合神经元、少突胶质细胞和小胶质细胞来生成一个微型集成大脑 芯片（miBrain 芯片）。在 UG3 Aim1.1 中，我们将建立代表健康和患病的 miBrain 芯片 通过结合最先进的生物聚合物的迭代优化来了解人脑的状态 以及来自麻省理工学院罗伯特·兰格实验室的工程专业知识。 UG3 Aim1.2将进行基因整合和验证 神经元活动的编码调制器和报告器使 miBrain 芯片能够研究神经元如何 活动受到影响，进而影响 AD 发病机制。 UG3 Aim2 将模拟病理 miBrain 芯片中男性和女性 SAD iPSC 系队列中 AD 的进展情况 匹配大脑样本、临床病史和基因组序列。我们将建立计算模型 描述导致最终状态的转录、细胞动力学和组织学转变 死后 AD 大脑。这些纵向病理图谱来自遗传多样性的健康人和季节性AD 个人将对AD发展产生机械性的洞察力，并创建一个发现和功效的平台 治疗方法的筛选。我们假设 AD 的机制受到以下因素的显着影响： 遗传变异性。在 UH3 中，我们将建立 APOE4 发病机制的潜在机制 (UH3 Aim1) 和 然后确定一组临床前和临床 AD 药物的功效、毒性和治疗窗 使用同基因 APOE3 和 APOE4 miBrain 芯片 (UH3 Aim2)。我们的多式联运战略将阐明如何 遗传变异影响 AD 发病机制和治疗反应，为治疗 AD 开辟了新途径 快速药物发现并将有效疗法转化为临床。