Human on a chip system to investigate genetic risk factors in Alzheimer's disease

项目总结/摘要 Hesperos将构建和测试具有循环血液和大脑的微型多器官系统。 脊髓液替代物，将提供洞察各种阿尔茨海默氏症表型对药物的反应， 以及外周效应对AD进展的影响，特别是ApoE变体。我们试图利用 博士摩根对老年痴呆症和衰老的研究联合收割机将其与谢利博士和希克曼对老年痴呆症的研究结合起来。 人类芯片系统，以更好地了解疾病及其作用机制，并测试疗效 和治疗的毒副作用。我们将研究小分子和生物制剂， 在相同的多器官系统中使用iPSC衍生的非疾病（ND）和阿尔茨海默病表型的模块。 一个可以准确预测人类反应的临床前模型不仅可以更好地决策， 其中老年痴呆症的治疗要考虑进入人体临床试验，还要针对个性化用药进行应用。 通过最终比较急性和慢性效应，该模型将能够预测临床试验的成功， 药效学（PD）模型，从临床前研究中为临床疾病试验提供信息。当前以人为本 体外毒性研究预测功能变化的能力有限， 许多潜在的治疗方法。我们之前已经构建了平台，展示了 多器官模拟急性反应，并将建立在这项技术上。 在这个第一阶段的提案中，我们将建立一个由皮层神经元组成的3器官系统， 长时程增强（LTP）作为功能性读出，其将被功能性血脑屏障隔开 (BBB)肝脏模型。肝脏将产生一个模型，不仅母体药物，但代谢物在 血液和血脑屏障将模拟药物及其代谢物进入脑的渗透。我们将使用 将APP突变引入iPSC并筛选和选择ApoE 3和ApoE 4的等基因方法 在系统与对照中测试的变体。神经元和肝脏中的突变和变异的影响将使 与CNS效应相反的外周效应。 开发一种低成本、易于使用的多器官系统来测定AD药物将有助于 广泛使用，并最大限度地提高药物开发社区的效益以及疗效， 用于患者特定治疗的毒理学评价。这些临床前测试系统的综合使用 和PBPK/PD模型提供了一个强大的工具，评估药物，衰老， 生物系统和疾病，并将促进合理的药物开发和临床试验设计。我们的团队 包含实现补助金目标所需的所有技能。在第二阶段，我们将扩大我们的实验， 急性到慢性，然后将其扩展到AD患者特异性样品，用于个性化药物应用。

Project Summary/Abstract Hesperos will construct and test microscale multi-organ systems with recirculating blood and cerebral spinal fluid surrogates that will give insights to the responses of various Alzheimer’s phenotypes to drugs as well as the influence of peripheral effects on AD progression, specifically ApoE variants. We seek to leverage Dr. Morgan’s research on Alzheimer’s and aging combine it with Drs. Shuler and Hickman’s research on human-on-a-chip systems to better understand the disease and its mechanism of action and to test efficacy and toxic side effects of treatments. We will investigate both small molecules and biologics, on human organ modules in the same multi-organ system using iPSC derived non-diseased (ND) and Alzheimer’s phenotypes. A preclinical model that can accurately predict human response should not only lead to better decisions on which Alzheimer’s treatment to take into human clinical trials, but also for personalized medicine applications. By eventually comparing acute to chronic effects, the model will enable prediction of clinical trial success using pharmacodynamic (PD) models to inform clinical disease trials from preclinical studies. Current human-based in vitro toxicity studies have the limited capacity to predict functional changes that have been the demise of many potential therapeutics. We have previously constructed platforms demonstrating the integration of multiple organ mimics for acute responses and will build upon that technology. In this Phase I proposal we will build a 3-organ system composed of cortical neuronal components to utilize long term potentiation (LTP) as a functional readout, which will be separated by a functional blood brain barrier (BBB) from a liver model. The liver will result in a model with not only parental drugs but metabolites in the blood and the BBB will model the penetration of the drug and its metabolites into the brain. We will use isogenic methods to introduce the APP mutation into iPSCs and screen and select for ApoE3 and ApoE4 variants to test in the system vs. control. The effect of mutation and variant in both neurons and liver will give insight to peripheral as opposed to CNS effects. Development of a low cost, easy to use multi-organ system to assay drugs for AD would facilitate widespread usage and maximize the benefit to the drug development community as well as for efficacy and toxicological evaluations for patient specific treatment. The integrated use of these pre-clinical test systems and PBPK/PD models provides a powerful tool for evaluating the dynamic interaction between drugs, aging biological system and disease and will facilitate rationale drug development and clinical trial design. Our team contains all of the skill sets to achieve the goals on the grant. In Phase II, we will expand our experiments from acute to chronic and then extend this to AD patient specific samples for personalized medicine applications.