A physiological and translational liver model to study the metabolism-modulating roles of extracellular matrix microstructures

摘要 我的实验室一直致力于开发生理相关但易于应用的组织 建模技术，探索细胞外基质（ECM）之间的相互作用， 微观结构和细胞代谢。基于最近的成功和发现，我们建议 开发更先进的肝脏建模技术，并深入研究纤维化相关的 ECM微结构可以损害肝脏代谢-前者旨在减少金钱/时间成本 和人类受试者在新药开发中的风险，后者将提供新的理解和 纤维化治疗的代谢靶点。虽然已经报道了各种微流体肝脏模型， 它们缺乏生理肝脏的关键成分，即所有必需的细胞类型， 相关架构和生理3D ECM。文献和我们的初步结果都表明， 这些成分在维持肝功能和体内平衡中起着至关重要的作用，这可能解释了 为什么目前的肝脏模型只能模拟部分功能。通过整合各种细胞类型， 蜂窝架构，并且3D ECM代表了可用技术的挑战性障碍。 因此，我们提出了一种创新的技术，以新的制造逻辑，工作流程， 和一套技术手段。这项技术将概括迄今为止大多数肝脏利基特性， 但是具有相对简单和直接的操作（设置、维护、分析等）。我们 最近首次报道，ECM微结构可以调节代谢活动， 各种细胞类型。基于此，我们建议建立ECM控制，模拟健康和纤维化 条件下，并彻底调查如何异常重塑ECM可以损害肝脏 新陈代谢还计划进行涉及整合素和AMP活化蛋白激酶的机制研究。 总而言之，还没有像所提出的那样的组织建模技术;而其他技术已经有了。 尚未报道ECM微观结构与细胞代谢之间的相互作用。建议的工作， 因此，代表了高度的新奇和我实验室在该领域的独特空间。完成所提出的 研究将对药物开发具有重要意义，因为新的测试/筛选平台 和代谢（代谢物和控制蛋白质）靶点将为未来的纤维化提供 治疗

ABSTRACT My laboratory has been dedicated to developing physiologically relevant yet easy-to-apply tissue modeling technologies, and exploring the interactions between extracellular matrix (ECM) microstructures and cell metabolisms. Building on recent successes and discoveries, we propose to develop a more advanced technology for liver modeling, and to profoundly study how fibrosis-relevant ECM microstructures can impair hepatic metabolism—the former aims to reduce the monetary/time costs and human subject risks in new drug development, and the latter will provide new understanding and metabolic targets for fibrosis treatments. Although various microfluidic liver models have been reported, they lack the critical compositions of the physiological liver, namely, all the necessary cell types, the relevant architecture, and physiological 3D ECMs. Both literature and our preliminary results suggest the crucial roles of these components in maintaining hepatic functions and homeostasis, which may explain why current liver models could only mimic part of the functions. Integrating the various cell types, the cellular architecture, and the 3D ECMs represents challenging hurdles by the available technologies. Therefore, we propose an innovative technology to model the liver with a new fabrication logic, workflow, and set of technical means. This technology will recapitulate the most liver niche properties heretofore, but with relatively simple and straightforward operations (setting up, maintenance, analyses, etc.). We recently reported for the first time that ECM microstructures could modulate metabolic activities in various cell types. Based on this, we propose to set up ECM controls that mimic healthy and fibrotic conditions, and thoroughly investigate how the aberrantly remodeled ECMs can impair hepatic metabolisms. Mechanistic studies involving integrins and AMP-activated protein kinase are also planned. To summarize, there has not been a tissue modeling technology like the proposed one; and others have not reported the interactions between ECM microstructures and cell metabolism. The proposed work, therefore, represents high novelty and my laboratory’s unique space in the field. Completing the proposed studies will be significant for pharmaceutical developments because a new testing/screening platform and metabolic (metabolites and the controlling proteins) targets will be provided for future fibrosis therapies.