The role of matrix-bound microvesicles in alcohol-related liver disease

基质结合微泡在酒精相关性肝病中的作用

• 批准号: 10582800
• 负责人: Gavin E Arteel
• 金额: $ 51.25万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582800
• 关键词: Affect; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcohols; Binding; Biodistribution; Biology; Biotin; Calpain; Cell Death; Cell Proliferation; Cells; Cirrhosis; Clinical; Data; Development; Disease; Disease Marker; Disease Progression; Dose; Exposure to; Extracellular Matrix; Extracellular Matrix Degradation; Fibrosis; Goals; Grant; Hepatic; Hepatocyte; Homeostasis; Human; Inflammation; Inflammatory; Inflammatory Response; Intervention; Knowledge; Label; Liver; Liver Fibrosis; Liver Regeneration; Liver diseases; Macrophage; Maintenance; Mediating; Messenger RNA; MicroRNAs; Mitochondria; Mus; Organ; Pathogenesis; Patients; Peptide Hydrolases; Phenotype; Play; Process; Production; Proteins; Proteome; Proteomics; RNA; Reaction; Regulation; Role; Signal Transduction; Signaling Molecule; Source; Testing; Therapeutic; Therapeutic Effect; Therapeutic Uses; Tissues; Translating; Translations; Vesicle; Work; acute liver injury; alcohol exposure; cell behavior; cell injury; cell regeneration; cell type; endoplasmic reticulum stress; experimental study; hepatoprotective; human disease; immunoregulation; in vivo; liver inflammation; liver injury; microvesicles; mouse model; nanoscale; nanovesicle; novel; pre-clinical; response; response to injury; stem cell differentiation; targeted treatment; tissue biomarkers; vesicular release

Alcohol-related liver disease (ALD) is a prevalent clinical problem, with many knowledge gaps in the pathogenesis of ALD, including the role and regulation of inflammatory and tissue reactions. Our overarching goal is to identify key new players in alcohol-mediated effects on development and progression of liver damage and fibrosis that could translate to targeted therapies. The extracellular matrix (ECM) and ECM dyshomeostasis are known to be important in ALD. ECM is produced by resident cells in the tissue/organ and contains a diverse range of components that create a dynamic and responsive microenvironment that regulates cell and tissue homeostasis. Our previous work demonstrated diverse qualitative and quantitative alterations to hepatic ECM during experimental ALD. In toto, alterations to the hepatic ECM are mediated not only by changes in ECM production, but also by changes in ECM degradation. We and others have demonstrated that even acute liver injury causes robust hepatic ECM changes. ECM also represents a potent reservoir of cell-signaling molecules that regulate cell behavior, determine cell phenotype and cell secretome, as well as influence inflammatory tissue responses. Numerous examples exist of cells dramatically changing their structural and functional phenotype when exposed to ECM different from their existing (normal or abnormal) ECM. By extension, changes to and/or altered turnover of hepatic ECM have potential to drive phenotypic changes in disease pathogenesis and progression. Work from our group shows that a major source of signaling molecules in ECM resides within matrix bound nanovesicles (MBV). MBV are nanometer-sized, membranous vesicles uniquely-bound within the ECM network. MBV contain and protect biologically active signaling molecules (miRNAs/proteins), and are known to play a role in immunomodulation, stem/progenitor cell differentiation, and maintenance of structurally normal and functional tissues. MBV likely play a fundamental role in tissue and organ organization across species and a regulatory role in the tissue response to injury. Our exciting preliminary studies show alcohol exposure dramatically alters hepatic MBV proteome and RNA/miRNA content. Similar changes are also seen in liver MBV isolated from ALD human explant livers vs liver MBV from non-ALD patients. We also show that liver MBV from alcohol-fed mice have differential effects on macrophage polarization and activation. Most importantly our preliminary findings suggest exogenous administration of MBV can significantly reduce alcohol-associated liver damage and inflammation. We hypothesize that MBV act not only as tissue biomarkers of ALD but are also important in regulating pathogenesis and disease progression. We will test this hypothesis via the following Specific Aims: 1. To analyze liver MBV biology in ALD.; 2. To understand mechanisms of liver MBV effects in ALD; 3. To test the ability of MBV to treat experimental ALD. Impact: Successful completion of the proposed work will identify unique MBV disease footprint and mechanisms of effects in liver and assess potential for therapeutic use of MBV in ALD.

酒精相关性肝病（ALD）是一种普遍的临床问题，在临床上存在许多知识空白。 ALD的发病机制，包括炎症和组织反应的作用和调节。我们的总体 目标是确定酒精介导的对肝脏发育和进展影响的关键新参与者 损伤和纤维化，可以转化为靶向治疗。细胞外基质（ECM）和ECM 在ALD中，已知内分泌失调是重要的。ECM由组织/器官中的常驻细胞产生， 包含各种各样的组件，这些组件创建了一个动态的、反应灵敏的微环境， 细胞和组织的稳态。我们以前的工作证明了不同的定性和定量改变， 实验性ALD期间的肝ECM。总的来说，肝ECM的改变不仅是由 在ECM的生产，而且还通过ECM降解的变化。我们和其他人已经证明， 肝损伤引起强烈的肝ECM变化。ECM也是细胞信号传导的有效储存库 调节细胞行为，决定细胞表型和细胞分泌组，以及影响 炎症组织反应。有许多例子表明，细胞的结构和功能发生了巨大的变化， 当暴露于不同于其现有（正常或异常）ECM的ECM时的功能表型。通过 肝ECM的延伸、变化和/或改变的周转有可能驱动表型变化， 疾病的发病机制和进展。我们小组的工作表明，信号分子的主要来源 在ECM中，该蛋白存在于基质结合纳米囊泡（MBV）内。MBV是纳米大小的膜囊泡 在ECM网络内绑定。MBV含有并保护生物活性信号分子 （miRNAs/蛋白质），并且已知在免疫调节、干/祖细胞分化和免疫调节中起作用。 维持结构正常和功能性组织。MBV可能在组织和器官中发挥重要作用 跨物种的组织和在组织对损伤的反应中的调节作用。我们激动人心的初步研究 显示酒精暴露显著改变肝MBV蛋白质组和RNA/miRNA含量。类似的变化还有 也见于从ALD人外植体肝分离的肝MBV与来自非ALD患者的肝MBV。我们也 显示来自酒精喂养小鼠的肝MBV对巨噬细胞极化和活化具有不同的作用。 最重要的是，我们的初步研究结果表明，外源性给予MBV可以显着减少 酒精相关的肝损伤和炎症。我们假设MBV不仅作为组织 这些基因是ALD的生物标志物，但在调节发病机制和疾病进展中也很重要。我们将 通过以下具体目标来检验这一假设：1.分析酒精性肝病患者肝脏MBV的生物学特性。2.了解 肝脏MBV在ALD中的作用机制; 3.探讨MBV对实验性ALD的治疗作用。影响力： 成功完成拟议的工作将确定独特的MBV疾病足迹和机制， 在肝脏中的作用，并评估MBV在ALD中的治疗用途的潜力。