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.

项目总结