Role of Lysosome Damage in ALD Pathogenesis

溶酶体损伤在 ALD 发病机制中的作用

• 批准号: 10668006
• 负责人: Paul Gideon Thomes
• 金额: --
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10668006
• 关键词: Acetaldehyde; Affect; Alcohol consumption; Alcoholic Liver Diseases; Alcohols; Aldehydes; Attention; Attenuated; Binding; Biogenesis; Biology; Cathepsins; Cell Death; Cell Death Induction; Cells; Cessation of life; Chemicals; Chronic; Circulation; Cytosol; Data; Disease; Disease Progression; Endocytosis; Enzymes; Ethanol; Etiology; Eukaryotic Cell; Extravasation; FDA approved; Functional disorder; Health; Heavy Drinking; Hepatocyte; Human; Hydrolase; Hydroxyl Radical; Impairment; Inflammasome; Inflammation; Inflammatory; Intervention; Investigation; Knowledge; Kupffer Cells; LAMP-1; Link; Liver; Liver diseases; Lysosomes; Macrophage; Malondialdehyde; Membrane; Membrane Proteins; Membrane Structure and Function; Methods; Mission; Molecular; Morbidity - disease rate; Mus; National Institute on Alcohol Abuse and Alcoholism; Natural Immunity; Organ; Organelles; Outcome; Outcomes Research; Pathogenesis; Pathology; Pathway interactions; Peptide Hydrolases; Persons; Pharmaceutical Preparations; Positioning Attribute; Procedures; Prognostic Marker; Proteins; Public Health; Quality Control; Recycling; Reporting; Research; Research Support; Rodent; Role; Signal Transduction; Superoxides; Testing; Tissues; adduct; alcohol exposure; cell injury; chronic alcohol ingestion; cytokine; cytotoxic; disease prognosis; drinking; feeding; hepatocyte injury; improved; liver inflammation; liver injury; lysosome membrane; macromolecule; mitochondrial dysfunction; mortality; new therapeutic target; novel; oxidation; prevent; repaired; response; targeted treatment

Abstract: Despite recent advances that have clarified the etiologies of alcohol-associated liver disease (ALD), the cellular and molecular alterations that lead to progressive liver damage are only partially understood. Furthermore, there are currently no FDA-approved therapies that block, or reverse ALD progression. Thus, it is urgent that we identify cellular and molecular mechanisms that contribute to progressive liver damage, to improve disease prognosis, and identify new treatment targets and procedures that alleviate or even prevent ALD. Heavy alcohol consumption affects all tissues, but it causes the greatest damage to the liver. This is because alcohol (ethanol or EtOH) is primarily metabolized in the liver to generate toxic products (acetaldehyde, superoxide, and hydroxyl radicals) that, with continued drinking, damage and impair the structure and function of membrane-bound organelles, including the ER, mitochondrion, and the lysosome. The latter organelle degrades nearly all macromolecules in eukaryotic cells. Our objective is to identify specific alterations induced by EtOH metabolite(s) that cause lysosome damage in hepatocytes and Kupffer cells (resident liver macrophages), and which leads to parenchymal cell death and inflammatory signaling, respectively. Lysosomes have a crucial role in cellular quality control, as they recycle obsolete proteins and dysfunctional organelles, including damaged lysosomes. If cells do not repair/remove damaged lysosomes, they will continue to leak their proteolytic enzymes to trigger cell death and provoke inflammatory signaling by Kupffer cells. We and others previously reported that chronic ethanol (EtOH) consumption causes faulty lysosome biogenesis and lysosomal membrane instability. Here, we show exciting new pilot data indicating that chronic EtOH consumption by both humans and rodents causes lysosomal membrane damage and subsequent leakage of lysosomal cathepsin(s) (and other hydrolases) that contribute to liver cell injury. Furthermore, such damage releases lysosomal membrane components into the circulation, which may be prognostic markers of liver injury. Our pilot data, presented herein, suggest that primary and/or secondary EtOH metabolites damage lysosomes in hepatocytes and Kupffer cells, inducing cathepsin leakage which contribute to cell death and inflammation. These novel observations support our hypothesis that chronic EtOH oxidation damages lysosomes, causing leakage of cytotoxic lysosomal hydrolases, thereby, contributing to liver injury and inflammation. To test our hypothesis, we propose the following Specific Aims: In Aim 1 we will define the mechanisms of EtOH-induced lysosome damage that incite hepatocyte injury. In Aim 2 we will investigate the mechanisms of EtOH-induced lysosome damage that incite inflammatory signaling in Kupffer cells. We anticipate that the outcome of this research will reveal novel mechanisms by which EtOH oxidation promotes the progression of liver pathology by damaging lysosomes.

抽象的： 尽管最近的进步阐明了酒精相关肝病（ALD）的病因，但 并且仅部分理解导致肝脏损伤的分子改变。此外，那里 目前尚无阻塞或反向ALD进展的FDA批准的疗法。因此，我们很迫切 确定有助于肝脏损害的细胞和分子机制，以改善疾病 预后，并确定减轻甚至防止ALD的新治疗目标和程序。 大量饮酒会影响所有组织，但会对肝脏造成最大的损害。这是因为 酒精（乙醇或ETOH）主要在肝脏中代谢以产生有毒产物（乙醛， 超氧化物和羟基自由基），持续饮酒，损害和损害结构和功能 膜结合的细胞器，包括ER，线粒体和溶酶体。后一个细胞器 真核细胞中几乎所有大分子降解。我们的目标是确定引起的特定更改 通过EtOH代谢产生肝细胞和kupffer细胞（常驻肝脏）造成溶酶体损伤的作用 巨噬细胞），分别导致实质细胞死亡和炎症信号传导。 溶酶体在细胞质量控制中具有至关重要的作用，因为它们回收过时的蛋白质和功能障碍 细胞器，包括受损的溶酶体。如果细胞不修复/去除受损的溶酶体，它们将继续 泄漏其蛋白水解酶以触发细胞死亡并引起库普弗细胞的炎症信号传导。 我们和其他人以前报道说，慢性乙醇（ETOH）的消耗会导致溶酶体生物发生故障 和溶酶体膜不稳定性。在这里，我们显示令人兴奋的新试点数据，表明慢性ETOH 人类和啮齿动物的消费均会造成溶酶体膜损伤，随后泄漏 溶酶体组织蛋白酶（S）（和其他水解酶）会导致肝细胞损伤。此外，这种损害 将溶酶体膜成分释放到循环中，这可能是肝损伤的预后标志物。 我们的试点数据，本文介绍，表明原发性和/或次级ETOH代谢物损害溶酶体 在肝细胞和kupffer细胞中，诱导组织蛋白酶泄漏，导致细胞死亡和炎症。 这些新颖的观察结果支持我们的假设，即慢性EtoH氧化会损害溶酶体，导致 细胞毒性溶酶体水解酶的泄漏，从而导致肝损伤和炎症。测试 我们的假设，我们提出以下具体目的： 在AIM 1中，我们将定义ETOH诱导的溶酶体损伤的机制，从而促进肝细胞损伤。 在AIM 2中，我们将研究ETOH诱导的溶酶体损伤的机制，从而促进炎症 库普弗细胞中的信号传导。 我们预计这项研究的结果将揭示EtOH氧化促进的新机制 肝脏病理学的进展通过损害溶酶体。