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

用于研究细胞外基质微结构的代谢调节作用的生理和转化肝脏模型

• 批准号: 10676333
• 负责人: Chengpeng Chen
• 金额: $ 33.41万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE COUNTY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-10 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676333
• 关键词: 3-Dimensional; 5' -AMP-activated protein kinase; Architecture; Cellular Metabolic Process; Dedications; Development; Extracellular Matrix; Fibrosis; Future; Hepatic; Homeostasis; Impairment; Integrins; Laboratories; Literature; Liver; Logic; Maintenance; Metabolic; Microfluidics; Modeling; Pharmacologic Substance; Physiological; Property; Proteins; Reporting; Research; Risk; Role; Structure; Technology; Testing; Time; Tissue Model; Work; cell type; cost; drug development; fabrication; human subject; innovative technologies; insight; liver metabolism; metabolic abnormality assessment; novel therapeutics; operation; screening; success; therapy development

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.

抽象的 我的实验室一直致力于开发生理相关且易于使用的组织 建模技术，并探索细胞外基质 (ECM) 之间的相互作用 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性如何 ECM微观结构会损害肝脏代谢——前者旨在降低金钱/时间成本 和新药开发中的人体受试者风险，后者将提供新的认识和 尽管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组成，即所有必需的细胞类型、 相关的架构和生理学 3D ECM。文献和我们的初步结果都表明了这一点。 这些成分在维持肝功能和体内平衡方面发挥着至关重要的作用，这可以解释 为什么当前的肝脏模型只能模拟部分功能，整合各种细胞类型。 蜂窝架构和 3D ECM 代表了现有技术的挑战性障碍。 因此，我们提出了一种创新技术，以新的制造逻辑、工作流程、 和一套技术手段，将概括迄今为止最肝脏的利基特性， 但操作相对简单明了（设置、维护、分析等）。 最近首次报道 ECM 微观结构可以调节代谢活动 基于此，我们建议建立模拟健康和纤维化细胞的 ECM 对照。 条件，并彻底研究异常重塑的 ECM 如何损害肝脏 还计划进行涉及整合素和 AMP 激活蛋白激酶的机制研究。 总而言之，目前还没有一种像所提出的技术和其他技术一样的组织建模技术。 没有报道ECM微观结构和细胞代谢之间的相互作用所提出的工作， 因此，代表了高度的新颖性和我的实验室在该领域的独特空间。 研究对于药物开发具有重要意义，因为新的测试/筛选平台 将为未来的纤维化提供代谢（代谢物和控制蛋白质）目标 疗法。