Re-engineering a human 3D liver tissue model for non-alcoholic fatty liver disease for drug screening

项目摘要 非酒精性脂肪性肝病（NAFLD）是一个全球性的公共卫生问题，发生在全球约25%的人群中。 成人人口。尽管制药业进行了大量投资，但目前还没有批准的药物用于 NAFLD的治疗，可能反映了涉及多种途径的异质性病理生理学。 我们最近实施了人类仿生，血管化肝腺泡微生理系统 使用全人原代肝细胞（肝细胞、肝窦内皮细胞、星状细胞和枯否细胞）， 细胞）。我们已经开始测试更多的 最近通过应用定量系统预测了100多种药物和药物组合 药理学（QSP）。我们也一直在努力实现所有iPSC衍生的肝细胞 来自将在开始拟定研究时完成的相同患者。使用患者- 特异性iPSC衍生的细胞对于产生用于精准医学的可再现的患者群体至关重要。我们也 利用微生理系统数据库（MPS Db）来管理、分析和确定 NAFLD实验模型的再现性。迫切需要制定和实施高质量的 基于iPSC衍生细胞的含量和通量NAFLD MPS模型， 再现性匹兹堡大学药物发现中心和 NCATS 3D组织生物打印实验室（3DTBL）将利用肝脏腺泡 通过开发基于生物打印的全iPS板的NAFLD模型， 最大化测试预测药物和组合的通量、模型功能和再现性 与选定的主要屏幕指标。我们还将生物打印现有高含量的中间层 vLAMPS，以提高该二级药物测试平台的再现性，该平台将使用 先前已经公布的指标，导致改进的化合物选择平台， 开发精确的NAFLD治疗方法。由于缺乏批准的治疗NAFLD的药物， 这在很大程度上是由于涉及多个途径的疾病的异质性病理学以及 不能完全重现人类疾病的动物模型。开发一个综合性高 通量和高含量NAFLD实验模型，用于预测药物的初步筛选和最佳 使用在transwell板中生物打印的人类、患者特异性iPSC衍生的肝细胞的组合将转化 从NAFLD药物发现到精准医疗的方法。对最佳药物的更详细分析 生物打印版本的vLAMPS模型中的药物组合将细化 药物/组合用于选择患者队列。

Project Summary Nonalcoholic fatty liver disease (NAFLD) is a worldwide public health problem, occurring in ~25% of the global adult population. Despite major investments by the pharmaceutical industry, there are no approved drugs for the treatment of NAFLD, probably reflecting the heterogeneous pathophysiology involving multiple pathways. We have recently implemented the human biomimetic, vascularized Liver Acinus Microphysiology System (vLAMPS) using all-human primary liver cells (hepatocytes, liver sinusoidal endothelial, stellate and Kupffer cells) from the same genotyped patients in a NAFLD experimental model. We have initiated the testing of more than 100 drugs and drug combinations recently predicted through the application of quantitative systems pharmacology (QSP). We have also been working toward the implementation of all iPSC-derived liver cells from the same patients that will be completed at the time of starting the proposed study. The use of patient- specific iPSC-derived cells is critical to produce reproducible patient cohorts for precision medicine. We also harness the Microphysiology Systems Database (MPS Db) to manage, analyze and to determine reproducibility of the NAFLD experimental models. There is a critical need to develop and implement high content and throughput NAFLD MPS models based on iPSC-derived cells that demonstrate maximal reproducibility. The goal of this collaborative effort between the University of Pittsburgh Drug Discovery Institute (UPDDI) and the NCATS 3D Tissue Bioprinting Laboratory (3DTBL) is to harness the liver acinus design into a higher throughput biomimetic by developing a bioprinted all-iPS plate-based, NAFLD model to maximize throughput of testing the predicted drugs and combinations, model functionality and reproducibility with selected primary screen metrics. We will also bioprint the middle layer of the existing high content vLAMPS to improve the reproducibility of this secondary drug testing platform that will use the full panel of metrics that have been previously published resulting in an improved compound selection platform for the development of precision NAFLD therapeutics. The lack of approved therapeutics for treatment of NAFLD is due in large part to the heterogenous pathology of the disease involving multiple pathways and the use of animal models that do not fully recapitulate the human disease. The development of a combined high throughput and high content NAFLD experimental model for a primary screen of predicted drugs and optimal combinations using human, patient-specific iPSC-derived liver cells bioprinted in transwell plates will transform the approach to NAFLD drug discovery to precision medicine. The more detailed analysis of the best drugs and drug combinations in the bioprinted version of the vLAMPS models will refine the selection of drugs/combinations for select patient cohorts.