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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的阿尔茨海默氏病（AD）是一种使人衰弱的脑部疾病，人类和经济成本惊人。尽管遗传研究越来越多地识别与AD相关的多态性，仍然没有清晰的图片分子和细胞参与者以及每个贡献AD的程度。遗传和 AD的分子复杂性以及在人体组织中实验揭示它的技术缺乏一种瓶颈收缩了治疗剂的发现及其成功转化为诊所。使用人类IPSC我们最近开发了体外血脑屏障（IBBB），并部署了它以发现机制导致遗传易感性脑淀粉样血管病（CAA）。与临床研究相同，我们发现APOE4是CAA和AD的最强遗传风险因素显着增加淀粉样蛋白在我们的IBBB中沉积。然后，我们工程组织的易干性使细胞原因解剖疾病。我们发现仅在周细胞中APOE4的表达足以增加脑血管淀粉样蛋白的积累。确定介导CAA风险的因果细胞，然后启用分子和生化研究建立了基本机制，并揭示了新的治疗机会减轻CAA的遗传风险和潜在的AD。在这里，我们将以我们的成功为基础，将IBBB作为一个脚手架;我们将结合神经元，少突胶质细胞和小胶质细胞，以生成微集成大脑芯片（mibrain-chip）。在UG3 AIM1.1中，我们将建立代表健康和患病的Mibrain-Chip 通过迭代优化的迭代回合，人脑的状态结合了最先进的生物聚合物以及麻省理工学院罗伯特·兰格（Robert Langer）实验室的工程专业知识。 UG3 AIM1.2将在遗传上整合和验证神经元活性的编码调节剂和记者，使晶状芯片能够研究神经元如何活性受到影响，进而影响AD发病机理。 UG3 AIM2将建模病理 Mibrain-Chips中AD的进展，跨过男性和女性SAD IPSC线的队列匹配的大脑样品，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国家的转录，细胞动力学和组织学转变验尸大脑。这些纵向病理图来自遗传多样的健康和悲伤的个人将产生有关AD开发的机械洞察力，并为发现和功效创建平台筛查治疗学。我们假设AD的机制受到了显着影响遗传变异性。在UH3中，我们将建立APOE4发病机理（UH3 AIM1）和然后确定临床前和临床广告药物面板的功效，毒性和治疗窗口使用ISEGENIC APOE3和APOE4 MIBRAIN-CHIPS（UH3 AIM2）。我们的多模式策略将阐明遗传变异影响AD发病机理和治疗反应，为迅速的药物发现和将有效疗法转化为诊所。