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.

目前，估计有十分之一的65岁及以上的美国人患有阿尔茨海默氏病（AD），但那里 仍然没有可用的药理治疗可以减慢或阻止AD中的神经元损害。许多药物 针对显示小鼠有望结果的AD未能预防临床试验的认知能力下降。我们 仍然不了解AD和当前体外系统的分子机制，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机制，并为改善临床结果提供了药物测试和发现的工具。 最近，合作者Li-huei Tsai开发了一个大脑模型，所有七种相关的神经细胞类型 （mibrain）。需要工程脑模拟水凝胶脚手架和将流入系统引入系统 增强身体相关性和细胞表型。一个新型的大脑模拟氢支架将是 与当前的替代方案不同，该工程不包含删除的细胞外矩阵（ECM）组件 像纤维蛋白原一样，将具有可调节的降解动力学和批处理变异性较小。 IPSC技术 将用于创建每个人都包含一个单个单个单元的模型，并将为个人创建 来自潜水员的遗传背景。将IPSC技术和大脑模仿脚手架结合在一起 平台，将导致一个可以研究AD机制和评估的系统 治疗。该模型将被部署以询问涉及APOE4促进发病机理的途径， 晚期发作AD的强遗传危险因素，评估APOE变体和关键分子的影响 AD病理特征的监管机构。该模型将进一步利用以评估ECM的效果 AD发病机理和ECM的轮廓变化的组成部分，因为AD与AD的变化有关，但 迄今为止，没有一个体外模型来探测这些变化的影响或原因。 这项工作将导致一种新型的灌注膜模型的发展，该模型可以利用进行研究和 测试AD的疗法，解剖潜在的分子途径并评估疾病发病机理和 神经元活性。组合的水凝胶脚手架，芯片平台和IPSC技术提供了强大的 模仿大脑的方法，可以迅速部署以探究与 神经血管机制，神经素类型相互作用和神经系统疾病。 在培训中，该项目可以综合田地，并以导致获得新专业知识的方式合并 每个区域都在开发一个具有许多潜在未来方向的新型研究小众市场时。该项目将是 在世界有信任的培训环境中执行，并通过全面的培训计划在内 技术，课程，会议，半小伙子，期刊俱乐部以及实验室和个人会议。这都是设计的 启动了开发技术的学术科学家职业，以探测神经生物学 机制，治疗发现和改善的疾病治疗以及培训未来科学家。