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Eyimer病（AD），但那里 仍然没有药理治疗可以减慢或阻止许多药物的神经元损害。 在小鼠中显示出有希望的结果的AD无法预防临床试验的认知能力下降 仍然不了解AD和当前体外系统的分子机制，无法重新分配 疾病的复杂性。 阐明AD机制，并为药物测试和椎间盘的临床结果提供了工具。 最近，合作者Li-huei Tsai Tsai开发了一种大脑模型，所有SEVENT神经细胞类型 （mibrain）。 增强生理相关性和细胞表型。 与当前的替代方案不同，该工程将不包含有害的细胞外基质（ECM）组件 像纤维蛋白原一样，可调节的降解动力学和批处理变异性较小 将创建每个模型，每个模型都包含一个单独的单元，并为个人创建 从不同的遗传背景结合了IPSC技术和脑模仿脚手架 平台，将导致一个可以研究AD机制和评估治疗的系统 处理该模型将被部署，以询问涉及APOE4的发病机理的途径 晚期AD的最强遗传因素 AD病理签名的调节器将进一步利用以评估ECM AD发病机理和ECM的轮廓变化的组件与AD的变化有关 迄今为止，没有一个体外模型来探测这些变化的影响的影响。 这项工作将导致一种新型的灌注模型的发展，该模型可以利用 测试AD的治疗剂，忽视潜在的分子途径并评估疾病发病机理和 神经元活动。 模仿大脑的方法，可以迅速部署以探究与 神经血管机制，神经细胞类型相互作用和神经系统疾病。 在培训中，该项目可以综合领域，以获得新的专业知识的方式合并 每个领域都在开发带有许多潜在的未来方向的新型研究局面。 在世界有信任的培训环境中执行，并制定了包括有用的培训计划 技术，课程，会议，研讨会，期刊俱乐部和实验室和个人会议。 启动学术科学家的职业发展技术，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。