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An inflammation-induced fibrosis-on-chip system for the testing of anti-fibrosis drugs

用于测试抗纤维化药物的炎症诱导纤维化芯片系统

基本信息

批准号：
10241534
负责人：
Ruogang Zhao
金额：
$ 45.24万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-15 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10241534
关键词：
Adhesions Animal Model Animals Automobile Driving Biological Markers Biological Models Biology Biomechanics Blood Vessels Cells Clinic Clinical Trials Collaborations Coupled Data Development Device or Instrument Development Disease Drug Delivery Systems Drug Screening Drug Targeting Event FDA approved Fibroblasts Fibrosis Goals Health Histology Human In Vitro Inflammation Inflammatory Joints Laboratories Lung Macrophage Activation Measurement Mediating Mediator of activation protein Microfluidics Modeling Myofibroblast Pathogenesis Pathology Pathway interactions Performance Pharmaceutical Preparations Process Publications Pulmonary Fibrosis Research Research Personnel Structure of parenchyma of lung Surface System Technology Testing Therapeutic Therapeutic Effect Tissue Engineering Tissue Model Tissues Translations Treatment Efficacy antifibrotic treatment base cell type comparative efficacy design drug action drug candidate drug discovery drug efficacy fibrogenesis idiopathic pulmonary fibrosis improved in vitro Model innovation interstitial macrophage monocyte novel novel strategies organ on a chip physiologic stressor pre-clinical preclinical development screening targeted treatment therapeutic target

项目摘要

Idiopathic pulmonary fibrosis (IPF), characterized by the progressive stiffening of lung tissues, is a severe disease with no cure. The understanding of the IPF pathogenesis is incomplete, but inflammation has been identified as one of the major mediators and has been proposed as a therapeutic target for the development of anti-IPF drugs. However, since existing in vitro fibrosis models are composed of limited cell types and utilize rigid 2D culture formats, they cannot recapitulate the interaction between multiple profibrotic cells (macrophage, myofibroblast) and the physiological stresses (shear flow, matrix stiffening, tissue contraction) in the fibrotic tissue. As a result, these models are not able to provide the efficacy readout on the “therapeutic targets” of the anti-fibrosis drugs. The objective of this renewal project is to develop a co-cultured fibrotic microtissue system that can model the fibrogenesis event caused by the inflammation and predict the therapeutic efficacy of the anti-fibrotic drugs that target inflammation pathways. Investigators have previously developed a static, mono- cultured fibrotic microtissue system that can recapitulate the late-stage fibrogenic changes in tissue biomechanics and histology caused by myofibroblast differentiation. However, this system is limited in predicting the efficacy of drugs that target important early stage fibrogenesis events. In the current project, investigators propose to expand the fibrosis modeling capacity of the existing system by including early-stage fibrogenesis events, such as flow-mediated profibrotic activation of the macrophages and inflammation induced myofibroblast differentiation. With this improved modeling capability, the new system will allow the examination of the drug efficacy on the inflammatory pathways, thus validating the mechanism of action of the drug on the intended target. The aims will include to develop a co-cultured fibrotic microtissue system that can model inflammation-induced fibrogenesis of the lung interstitial tissue and to evaluate the screening capacity of the microtissue system for anti-fibrosis drugs that target the inflammatory pathway. It is expected that such a system will be able to simulate the therapeutic effects of the drug candidates on inflammatory pathways, thus allowing the delineation of the therapeutic mechanism of the drug. Such a new approach can significantly expedite the translation of anti-fibrotic therapies from the laboratories to the clinics. 1

特发性肺纤维化（IPF）是一种严重的肺疾病，以肺组织的进行性硬化为特征