Regulation of Ductular Reaction by Substance P during Alcohol-induced Liver Injury

P物质对酒精性肝损伤过程中小管反应的调节

• 批准号: 10592570
• 负责人: Gianfranco D Alpini
• 金额: $ 23.69万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10592570
• 关键词: 3-Dimensional; Address; Affect; Afferent Neurons; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcoholic steatohepatitis; Alcohols; Attention; Biliary; Biological; Cell Aging; Cell Proliferation; Cells; Cholestasis; Chronic; Cirrhosis; Country; Coupled; Critical Pathways; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Development; Disease Progression; Drug usage; Electronic Mail; Enzymes; Epithelial Cells; Ethanol; FDA approved; Fatty Liver; Fatty acid glycerol esters; Female; Fibrosis; Functional disorder; GTP-Binding Proteins; Genes; Goals; Hepatic; Hepatic Stellate Cell; Hepatocyte; Human; Infiltration; Inflammation; Inflammatory; Inflammatory Infiltrate; Knockout Mice; Knowledge; Kupffer Cells; Liver; Liver Failure; Liver Fibrosis; Liver diseases; Macrophage; Measures; Modeling; Morbidity - disease rate; Mus; National Institute on Alcohol Abuse and Alcoholism; Nausea and Vomiting; Neuropeptides; Organoids; Outcome; PPAR gamma; Pathogenesis; Pathology; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Phenotype; Play; Primary carcinoma of the liver cells; Proliferating; Reaction; Receptor Signaling; Regulation; Repression; Role; SIRT1 gene; Sampling; Serum; Signal Transduction; Steatohepatitis; Substance P; System; TACR1 gene; Tachykinin; Testing; Therapeutic; Tissues; United States; Up-Regulation; Work; alcohol effect; antagonist; aprepitant; cell type; chemotherapy; cholangiocyte; chronic liver disease; feeding; immune activation; immune cell infiltrate; immunoreactivity; in vivo; knock-down; lipid biosynthesis; liver injury; male; mortality; mouse model; neuroendocrine phenotype; neuroinflammation; neutrophil; non-alcoholic fatty liver disease; novel; novel therapeutic intervention; paracrine; pharmacologic; prevent; receptor; receptor expression; recruit; response; senescence; sex; simple steatosis

Alcohol-associated liver disease (ALD) is one of the leading causes of chronic liver disease in Western countries. ALD is associated with increased mortality due to a broad spectrum of hepatic pathologies ranging from simple steatosis to alcoholic steatohepatitis (ASH), alcoholic hepatitis (AH), cirrhosis, and hepatocellular carcinoma. Recent studies have drawn attention to other factors contributing to ALD, including alterations in the vasculature, portal tract inflammation and peribiliary fibrosis, and ductular reaction (i.e., activation of the neuroendocrine phenotype of cholangiocytes). However, very little information is known about the effects of alcohol on biliary epithelial cells (i.e., cholangiocytes). Substance P (SP) is a neuropeptide secreted predominantly from sensory neurons and is known to play a key role in neuroinflammation via the recruitment and activation of immune cells. Previous studies have shown an upregulation of the SP/NK1R axis in cholangiocytes in response to liver injury due to cholestasis and that SP regulates cholangiocyte proliferation via cAMP/PKA signaling. SP has been shown to increase hepatic fibrosis via differential changes in cholangiocytes and hepatic stellate cell (HSCs) senescence. However, the SP/NK1R axis's role in ALD has not been explored. Based on novel preliminary data, the central hypothesis is that ALD-induced ductular reaction triggers a neuroendocrine phenotype in cholangiocytes whereby secretion of SP stimulates hepatic steatosis and fibrosis and increases infiltration and activation of immune cells occurs during the progression of ALD in proposed. To address the central hypothesis, two specific aims are proposed: 1) determine the expression and distribution of SP/NK1R axis during the progression of ALD in human samples and a mouse model of alcohol- induced liver injury; and 2) determine the therapeutic potential of the knockdown and/or pharmacological inhibition of the SP/NK1R axis in a mouse model of ALD and human ALD-derived liver organoids. The expected outcome of this work is an understanding of the role of the SP/NK1 axis and downstream signaling mechanisms in the pathogenesis of ALD. The successful completion of the proposed studies will have a significant positive impact on the knowledge of factors regulating ductular reaction observed in ALD and lay the groundwork for developing novel therapeutic approaches for ALD.

酒精相关性肝病（ALD）是西方国家慢性肝病的主要原因之一 国家。 ALD 与多种肝脏病理导致的死亡率增加相关 从单纯性脂肪变性到酒精性脂肪性肝炎 (ASH)、酒精性肝炎 (AH)、肝硬化和肝细胞性脂肪肝 癌。最近的研究引起了人们对导致 ALD 的其他因素的关注，包括 脉管系统、门静脉炎症和胆周纤维化以及导管反应（即激活 胆管细胞的神经内分泌表型）。然而，关于其影响的信息知之甚少。 酒精对胆管上皮细胞（即胆管细胞）的影响。 P物质（SP）是一种分泌的神经肽 主要来自感觉神经元，已知通过募集在神经炎症中发挥关键作用 和免疫细胞的激活。先前的研究表明 SP/NK1R 轴的上调 胆管细胞对胆汁淤积引起的肝损伤的反应，SP 调节胆管细胞增殖 通过 cAMP/PKA 信号传导。 SP 已被证明可通过不同的变化来增加肝纤维化 胆管细胞和肝星状细胞（HSC）衰老。然而，SP/NK1R 轴在 ALD 中的作用尚未明确。 被探索过。基于新的初步数据，中心假设是 ALD 诱导的导管反应 触发胆管细胞的神经内分泌表型，从而分泌 SP 刺激肝脂肪变性 在 ALD 进展过程中，会发生纤维化并增加免疫细胞的浸润和激活 建议的。为了解决中心假设，提出了两个具体目标：1）确定表达式和 人类样本和酒精小鼠模型中 ALD 进展过程中 SP/NK1R 轴的分布 诱发肝损伤； 2) 确定敲低和/或药理学的治疗潜力 在 ALD 小鼠模型和人 ALD 衍生的肝脏类器官中抑制 SP/NK1R 轴。这 这项工作的预期成果是了解 SP/NK1 轴和下游信号传导的作用 ALD 的发病机制。拟议研究的成功完成将有 对 ALD 中观察到的调节导管反应的因素的了解产生显着的积极影响，并奠定了 为开发新的 ALD 治疗方法奠定了基础。