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

项目摘要/摘要 Hesperos将建造和测试具有循环血液和大脑的微型多器官系统 脊髓液替代物将深入了解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，特别是载脂蛋白E变体。我们试图利用 摩根博士对阿尔茨海默氏症和衰老的研究与舒勒和希克曼博士对阿尔茨海默病和衰老的研究相结合 芯片人系统，以更好地了解疾病及其作用机制并测试疗效 以及治疗的毒副作用。我们将研究小分子和生物制品对人体器官的影响。 同一多器官系统中的模块使用IPSC衍生的非疾病(ND)和阿尔茨海默氏症表型。 能够准确预测人类反应的临床前模型不仅应该带来更好的决策 其中阿尔茨海默氏症的治疗将进入人体临床试验，也可用于个性化药物应用。 通过最终比较急性和慢性影响，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 体外毒性研究对预测已经死亡的功能变化的能力有限。 很多潜在的治疗方法。我们之前已经构建了平台，演示了 多个器官模拟急性反应，并将建立在这项技术的基础上。 在这个第一阶段的提案中，我们将构建一个由皮质神经元组件组成的三器官系统，以利用 长时程增强(LTP)作为功能读出，它将被功能血脑屏障隔开 (Bbb)来自肝脏模型。肝脏将导致一个模型，不仅有亲本药物，而且有代谢产物 血液和血脑屏障将模拟药物及其代谢物进入大脑的渗透情况。我们将使用 将APP基因突变导入IPSCs的方法及ApoE3、ApoE4基因的筛选 在系统和控制中测试的变体。神经元和肝脏中突变和变异的影响将会给 洞察到外周，而不是中枢神经系统的影响。 开发一种低成本、易使用的多器官系统来检测AD药物将有助于 广泛使用，并最大限度地造福于药物开发界以及有效性和 用于患者特定治疗的毒理学评估。这些临床前测试系统的综合使用 而PBPK/PD模型为评价药物与衰老之间的动态相互作用提供了有力的工具 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 包含实现奖助金目标的所有技能集。在第二阶段，我们将扩大我们的实验范围 从急性到慢性，然后将其扩展到AD患者特定的样本，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.