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

设计用于探测和评估阿尔茨海默病机制的血管化脑芯片

• 批准号: 10428479
• 负责人: Alice Stanton
• 金额: $ 6.76万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10428479
• 关键词: Address; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease therapeutic; American; Amyloid; Area; Astrocytes; Basement membrane; Binding; Biochemical; Biocompatible Materials; Blood Vessels; Brain; Brain Diseases; Cell physiology; Cells; Chondroitin Sulfates; Clinical; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Coculture Techniques; Cognitive; Collaborations; Collagen; Complex; Cues; Deposition; Development; Devices; Disease; Disease Outcome; Drug Targeting; Endothelium; Engineering; Environment; Extracellular Matrix; Fibrinogen; Fibronectins; Future; Gene Expression; Genetic; Health Care Costs; Heparan Sulfate Proteoglycan; Hippocampus (Brain); Human; Hyaluronic Acid; Hydrogels; Impaired cognition; In Vitro; Individual; Journals; Kinetics; Laminin; Late Onset Alzheimer Disease; Lead; Maintenance; Mechanics; Membrane Proteins; Microfluidic Microchips; Modeling; Molecular; Monitor; Mus; Neurofibrillary Tangles; Neuroglia; Neurons; Neurosciences; Outcome; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Peptides; Pericytes; Permeability; Persons; Pharmacological Treatment; Phenotype; Physiological; Polyethylene Glycols; Research; Risk Factors; Scientist; Stereotyping; Synapses; System; Techniques; Technology; Testing; Therapeutic; Training; Variant; Vascular Permeabilities; Work; blood-brain barrier permeabilization; brain morphology; career; cell type; cerebral microvasculature; crosslink; delivery vehicle; design; drug discovery; drug testing; foot; genetic risk factor; human old age (65+); hydrogel scaffold; improved; in vitro Model; in vivo; induced pluripotent stem cell; induced pluripotent stem cell technology; insight; janusin; meetings; mimetics; myelination; nervous system disorder; neurobiological mechanism; neuronal excitability; neurovascular; novel; prevent; scaffold; symposium; tau aggregation; therapeutic evaluation; tool; training project

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.

据估计，65 岁及以上的美国人中，目前有十分之一患有阿尔茨海默病 (AD)，但 仍然没有可用的药物治疗可以减缓或阻止 AD 的神经元损伤。多种药物 在临床试验中，针对 AD 的药物在小鼠身上显示出可喜的结果，但未能阻止认知能力下降。我们 仍然不了解 AD 背后的分子机制，并且当前的体外系统无法概括 疾病的复杂性。概括 AD 病理学的体外人脑模型可以使 阐明 AD 的机制，并为药物测试和发现提供工具，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 （米脑）。需要设计一种仿脑水凝胶支架并将流量引入系统中 增强生理相关性和细胞表型。一种新型的类脑水凝胶支架将 与目前的替代品不同，它不会含有有害的细胞外基质 (ECM) 成分 像纤维蛋白原一样，具有可调节的降解动力学和较小的批次间变异性。 iPSC技术 将用于创建模型，每个模型都包含来自单个个体的细胞，并且将为个体创建 来自不同的遗传背景。将 iPSC 技术与可灌注的拟脑支架相结合 平台，将产生一个能够研究 AD 机制和评估治疗的系统 治疗。该模型将用于探究涉及 APOE4 促进的发病机制的途径， 迟发性 AD 的最强遗传风险因素，评估 APOE 变异和关键分子的影响 AD 病理特征的监管者。该模型将进一步用于评估 ECM 的效果 AD 发病机制的组成部分和 ECM 的变化，因为 AD 与 AD 的变化相关，但 迄今为止，还没有体外模型来探讨这些变化的影响或原因。 这项工作将开发出一种新型可灌注 miBrain 模型，可用于研究和 测试 AD 疗法，剖析潜在的分子途径并评估疾病发病机制和 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 模仿大脑的方法可以快速部署来探索与以下问题相关的各种问题 神经血管机制、神经细胞类型相互作用和神经系统疾病。 对于培训而言，该项目能够综合各个领域，并以多种方式组合起来，从而获得以下领域的新专业知识： 每个领域，同时开发一个具有许多潜在未来方向的新颖的研究领域。该项目将是 在世界知名的培训环境中执行，并制定全面的培训计划，其中包括有用的 技术、课程、会议、研讨会、期刊俱乐部以及实验室和个人会议。这都是设计好的 开启学术科学家的职业生涯，开发能够探索神经生物学的技术 机制、治疗发现、改进的疾病治疗以及培训未来的科学家。