Engineering a Vascularized Brain-Chip for Probing and Evaluating Mechanisms of Alzheimer’s Disease

据估计，65岁及以上的美国人中有十分之一目前患有阿尔茨海默病（AD）， 目前还没有药物治疗可以减缓或阻止AD中的神经元损伤。许多药物 在小鼠中显示出有希望结果的靶向AD在临床试验中未能预防认知能力下降。我们 仍然不了解AD的分子机制，并且目前的体外系统不能概括 疾病的复杂性。一种概括AD病理学的体外人脑模型可以使 阐明AD的机制，并提供药物测试和发现的工具，以改善临床结果。 最近，合作者Li-Huei Tsai开发了一个包含所有七种相关神经细胞类型的大脑模型 （miBrain）.设计脑模拟水凝胶支架并将流动引入系统是期望的， 增强生理相关性和细胞表型。一种新型的脑模拟水凝胶支架将是 工程化的，与当前的替代品不同，其将不包含有害的细胞外基质（ECM）组分 类似于纤维蛋白原，并且具有可调的降解动力学和较少的批次间变异性。iPSC技术 将用于创建模型，每个模型包含来自单个个体的细胞，并将为个体创建 来自不同的遗传背景。iPSC技术和脑模拟支架在可灌注 平台，将导致一个系统，可以使研究AD机制和评估治疗 治疗。该模型将用于研究涉及APOE 4促进的发病机制的途径， 晚发性AD最强的遗传风险因素，评估APOE变异和关键分子的影响， 调节剂对AD病理特征的影响。该模型将进一步用于评估ECM的效果 成分对AD发病机制和ECM中的概况变化的影响，因为AD与AD中的变化相关， 迄今为止，还没有体外模型来探测这些变化的影响或原因。 这项工作将导致开发一种新的可灌注miBrain模型，可以利用该模型进行研究， 测试AD的治疗方法，剖析潜在的分子途径并评估疾病的发病机制， 神经元活动组合的水凝胶支架、芯片平台和iPSC技术提供了强大的 一种模拟大脑的方法，可以快速部署，以探索各种各样的问题， 神经血管机制、神经细胞类型相互作用和神经系统疾病。 在培训方面，该项目使各领域能够综合起来，以获得新的专门知识的方式结合起来， 每个领域，同时开发一个新的研究利基与许多潜在的未来方向。该项目将 在世界知名的培训环境中执行，并有一个全面的培训计划，其中包括有用的 技术，课程，会议，研讨会，期刊俱乐部，实验室和个人会议。这一切都是为了 开启学术科学家的职业生涯，开发技术， 机制，治疗发现和改进疾病治疗以及培养未来科学家。

An estimated 1 in 10 Americans age 65 and older are currently living with Alzheimer’s Disease (AD), yet there is still no pharmacologic treatment available that can slow or stop the neuronal damage in AD. A number of drugs targeting AD that showed promising results in mice have failed to prevent cognitive decline in clinical trials. We still do not understand the molecular mechanisms underlying AD and current in vitro systems fail to recapitulate the complexity of the disease. An in vitro human brain model that recapitulates AD pathology could enable the elucidation of mechanisms of AD and provide a tool for drug testing and discovery for improved clinical outcomes. Recently, collaborator Li-Huei Tsai developed a model of the brain with all seven relevant neural cell types (miBrain). Engineering a brain-mimetic hydrogel scaffold and introducing flow into the system are desired to enhance the physiological relevance and cell phenotypes. A novel brain-mimetic hydrogel scaffold will be engineered, which, unlike current alternatives, will not contain deleterious extracellular matrix (ECM) components like fibrinogen and will have tunable degradation kinetics and less batch-to-batch variability. iPSC technology will be used to create models that each contain cells from a single individual and that will be created for individuals from diverse genetic backgrounds. Combining iPSC technology and a brain-mimetic scaffold in a perfusable platform, will result in a system that could enable the study of AD mechanisms and evaluation of therapeutic treatments. This model will be deployed to interrogate the pathway involving APOE4-promoted pathogenesis, the strongest genetic risk factor for late-onset AD, assessing the impact of APOE variant and key molecular regulators on AD pathological signatures. The model will be further harnessed to assess the effect of ECM components on AD pathogenesis and profile changes in ECM, as AD is associated with changes in AD but heretofore there has not been an in vitro model to probe the effects or causes of these changes. This work will result in the development of a novel perfusable miBrain model that can be harnessed to study and test therapeutics for AD, dissecting underlying molecular pathways and assessing disease pathogenesis and neuronal activity. The combined hydrogel scaffold, chip platform, and iPSC technology provide a powerful approach to mimicking the brain that can be rapidly deployed to probe a broad variety of questions related to neurovascular mechanisms, neural cell type interactions, and neurological diseases. For training, this project enables the synthesis of fields, combined in ways that lead to gaining new expertise in each area while developing a novel research niche with many potential future directions. The project will be executed in a world-renown training environment and with a comprehensive training plan that includes helpful techniques, courses, conferences, seminars, journal clubs, and lab and individual meetings. This is all designed to launch an academic scientist career of developing technologies that enable probing neurobiological mechanisms, therapeutic discovery, and improved disease treatments and of training future scientists.