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.

项目概要 非酒精性脂肪性肝病 (NAFLD) 是一个世界性的公共卫生问题，发生在全球约 25% 的人口中 成年人口。尽管制药行业进行了大量投资，但尚无批准用于治疗的药物 NAFLD 的治疗可能反映了涉及多种途径的异质病理生理学。 我们最近实施了人体仿生血管化肝腺泡微生理系统 (vLAMPS) 使用全人类原代肝细胞（肝细胞、肝窦内皮细胞、星状细胞和 Kupffer 细胞） 细胞）来自 NAFLD 实验模型中相同基因分型的患者。我们已经开始测试更多 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）。我们还一直致力于实现所有 iPSC 衍生的肝细胞 来自将在开始拟议研究时完成的相同患者。使用病人- 特定的 iPSC 衍生细胞对于产生可重复的精准医疗患者群体至关重要。我们也 利用微生理学系统数据库 (MPS Db) 来管理、分析和确定 NAFLD 实验模型的再现性。迫切需要开发和实施高 基于 iPSC 衍生细胞的 NAFLD MPS 模型，展示了最大的内容和吞吐量 再现性。匹兹堡大学药物发现部之间合作的目标 研究所 (UPDDI) 和 NCATS 3D 组织生物打印实验室 (3DTBL) 将利用肝腺泡 通过开发基于生物打印的全 iPS 板的 NAFLD 模型，设计成更高通量的仿生模型 最大限度地提高测试预测药物和组合、模型功能和再现性的吞吐量 与选定的主屏幕指标。我们还将对现有高含量的中间层进行生物打印 vLAMPS 旨在提高该二级药物测试平台的可重复性，该平台将使用完整的面板 之前发布的指标改进了化合物选择平台 开发NAFLD精准疗法。缺乏经批准的 NAFLD 治疗方法 很大程度上是由于该疾病的异质病理学涉及多种途径和使用 动物模型不能完全再现人类疾病。发展联合高 用于预测药物和最佳药物初步筛选的通量和高含量 NAFLD 实验模型 使用 Transwell 板中生物打印的人类、患者特异性 iPSC 衍生肝细胞的组合将发生转变 NAFLD 药物发现到精准医学的方法。对最佳药物的更详细分析 vLAMPS 模型生物打印版本中的药物组合将完善药物的选择 针对特定患者群体的药物/组合。