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

重新设计非酒精性脂肪肝的人体 3D 肝组织模型用于药物筛选

• 批准号: 10656213
• 负责人: Mark T. Miedel
• 金额: $ 42.84万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10656213
• 关键词: 3-Dimensional; Adult; Animal Model; Biological Assay; Biological Models; Biomimetics; Biosensor; Cells; Collaborations; Collagen; Collagen Type I; Database Management Systems; Development; Disease; Disease Pathway; Disease model; Drug Combinations; Drug Controls; Drug Industry; Drug Modelings; Drug Screening; Drug Targeting; Endothelial Cells; Engineering; Evaluation; Experimental Models; Fibrosis; Functional disorder; Goals; Hepatocyte; Human; Inflammation; Insulin Resistance; Investments; Kupffer Cells; Laboratories; Lipids; Liver; Methodology; Microfluidics; Modeling; National Center for Advancing Translational Sciences; Pathology; Pathway interactions; Patient Selection; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Population; Probability; Proteins; Public Health; Publishing; Reproducibility; System; Testing; Therapeutic; Time; Tissue Model; Tissues; Universities; Vascularization; bioprinting; cohort; design; disease phenotype; drug discovery; drug testing; genotyped patients; hepatic acinus structure; human disease; improved; induced pluripotent stem cell; microphysiology system; non-alcoholic fatty liver disease; precision medicine; progression marker; response; scale up; small molecule libraries; stellate cell

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.

项目摘要 非酒精性脂肪肝病（NAFLD）是全球公共卫生问题，发生在全球范围的25％中 成人人口。尽管制药行业进行了大量投资，但仍未获得批准的药物 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的仿生，血管化肝脏腺泡体生理系统 （vlamps）使用全人类原代肝细胞（肝细胞，肝窦内皮，星状和库普弗 在NAFLD实验模型中，来自同一基因分型患者的细胞）。我们已经启动了更多测试 最近通过应用定量系统预测的100种药物和药物组合 药理学（QSP）。我们还一直在努力实施所有IPSC衍生的肝细胞 从同一患者开始，该患者将在开始拟议的研究时完成。使用患者 特定的IPSC衍生细胞对于生产可再现的患者同类群至关重要。我们也是 利用微生物生理系统数据库（MPS DB）来管理，分析和确定 NAFLD实验模型的可重复性。有迫切需要开发和实施高 基于IPSC衍生的单元格的内容和吞吐量NAFLD MPS模型 可重复性。匹兹堡大学药物发现之间的合作努力的目标 Institute（UPDDI）和NCATS 3D组织生物打印实验室（3DTBL）是要利用肝脏 通过开发基于All-IPS的NAFLD模型来设计成较高的吞吐量仿生型 最大化测试预测的药物和组合，模型功能和可重复性的吞吐量 使用选定的主屏幕指标。我们还将在现有高素质的中间层生物。 VLAMP提高此二级药物测试平台的可重复性，该平台将使用完整的面板 以前已发布的指标，导致了改进的复合选择平台 开发精度NAFLD治疗剂。缺乏用于治疗NAFLD的批准的治疗剂是 在很大程度上是由于疾病的异源病理，涉及多个途径以及使用 无法完全概括人类疾病的动物模型。共同发展的发展 吞吐量和高含量的NAFLD实验模型，用于预测药物的主要屏幕 使用人类特异性IPSC衍生的肝细胞在Transwell板上生物打印的组合将转换 NAFLD药物发现的方法。对最佳药物的更详细分析 Vlamps模型的生物打印版本中的药物组合将完善选择的选择 精选患者队列的药物/组合。