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 我的实验室致力于开发与身体相关但易于贴面的组织 建模技术，并探索细胞外基质（ECM）之间的相互作用 微结构和细胞代谢。在最近的成功和发现的基础上，我们建议 开发一种更先进的技术来进行肝建模，并深刻研究与纤维化相关的如何 ECM微观结构可能会损害肝脏代谢 - 前者的目标是降低货币/时间成本 新药开发中的人类受试者风险，后者将提供新的理解和 纤维化治疗的代谢靶标。尽管已经报道了各种微流体肝模型，但 他们缺乏物理肝的关键组成，即所有必要的细胞类型， 相关体系结构和物理3D ECM。文学和我们的初步结果都表明 这些成分在维持肝功能和体内稳态中的关键作用，这可以解释 为什么当前的肝模型只能模仿功能的部分。整合各种单元类型， 蜂窝结构和3D ECM代表可用技术的挑战障碍。 因此，我们提出了一种创新的技术，以使用新的制造逻辑，工作流程对肝脏进行建模 和一组技术手段。这项技术将概括迄今为止最大的肝小众特性， 但是，采用相对简单明了的操作（设置，维护，分析等）。我们 最近首次报道了ECM微观结构可以调节代谢活动 各种细胞类型。基于此，我们建议建立模仿健康和纤维化的ECM控件 条件，并彻底研究异常重塑的ECM如何损害肝 代谢。还计划了涉及整联蛋白和AMP激活蛋白激酶的机械研究。 总而言之，没有像拟议中的组织建模技术。还有其他人 未报告ECM微结构与细胞代谢之间的相互作用。提议的工作， 因此，代表了高新颖的新颖性和我实验室在该领域的独特空间。完成建议 由于新的测试/筛选平台，研究对药物开发非常重要 将提供未来纤维化的代谢（代谢产物和控制蛋白）靶标 疗法。