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：
10054573
负责人：
Ruogang Zhao
金额：
$ 46.1万
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 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10054573
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 Physiological Process Publications Pulmonary Fibrosis Research Research Personnel Stress Structure of parenchyma of lung Surface System Technology Testing Therapeutic Therapeutic Effect Tissue Engineering Tissue Model Tissues Translations Treatment Efficacy 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 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）是一种严重的疾病，其特征是肺组织进行性硬化。对 IPF 发病机制的了解尚不完整，但炎症已经得到了证实。被确定为主要介质之一，并已被提议作为开发的治疗靶点然而，由于现有的体外纤维化模型由有限的细胞类型组成并且利用由于严格的 2D 培养格式，它们无法概括多个促纤维化细胞（巨噬细胞、肌成纤维细胞）和纤维化过程中的生理应力（剪切流、基质硬化、组织收缩）因此，这些模型无法提供“治疗目标”的功效读数。该更新项目的目标是开发共培养的纤维化微组织系统。可以模拟炎症引起的纤维发生事件并预测治疗效果研究人员之前开发了一种针对炎症途径的抗纤维化药物。培养的纤维化微组织系统，可以重现组织的晚期纤维化变化然而，该系统在肌成纤维细胞分化引起的生物力学和组织学方面受到限制。预测针对重要早期纤维发生事件的药物的功效。研究人员建议通过纳入早期阶段来扩展现有系统的纤维化建模能力纤维发生事件，例如巨噬细胞的流介导的促纤维化激活和诱导的炎症凭借这种改进的建模能力，新系统将允许进行检查。从而验证药物对炎症通路的作用机制目标将包括开发一种可以建模的共培养纤维化微组织系统。炎症诱导的肺间质组织纤维化并评估筛选能力预计这种针对炎症途径的抗纤维化药物的微组织系统。系统将能够模拟候选药物对炎症途径的治疗作用，从而这种新方法可以显着描述药物的治疗机制。加快抗纤维化疗法从实验室到临床的转化。 1