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.

酒精性肝病(ALD)是西方国家慢性肝病的主要病因之一 国家。由于广泛的肝脏病理变化，ALD与死亡率增加有关。 从单纯性脂肪变性到酒精性脂肪性肝炎(ASH)、酒精性肝炎(AH)、肝硬化和肝细胞癌 癌症。最近的研究已经引起了人们对导致ALD的其他因素的关注，包括 血管系统、门管炎和胆管周围纤维化，以及胆管反应(即 胆管细胞的神经内分泌表型)。然而，人们对艾滋病的影响知之甚少 酒精对胆管上皮细胞(即胆管细胞)的影响。P物质(SP)是一种神经肽 主要来自感觉神经元，已知通过募集在神经炎症中起关键作用 和免疫细胞的激活。先前的研究表明，SP/NK1R轴在 胆管细胞对胆汁淤积性肝损伤的反应及SP对胆管细胞增殖的调节 通过cAMP/PKA信号。SP已被证明通过不同的改变增加肝纤维化。 胆管细胞和肝星状细胞(HSCs)衰老。然而，SP/NK1R轴在ALD中的作用并没有 已经被探索过了。根据新的初步数据，中心假设是ALD诱导的胆管反应 在胆管细胞中触发神经内分泌表型，从而分泌SP刺激肝脏脂肪变性 在ALD的进展过程中，ALD发生纤维化并增加免疫细胞的渗透和激活 建议。为了解决中心假设，提出了两个具体的目标：1)确定表达式和 酒精性肝病进展过程中SP/NK1R轴在人和小鼠模型中的分布 诱导的肝损伤；以及2)确定击倒和/或药理作用的治疗潜力 在ALD小鼠模型和人ALD衍生的肝脏器官中抑制SP/NK1R轴。这个 这项工作的预期结果是理解SP/NK1轴和下游信号转导的作用 酒精性肝病的发病机制。建议的研究若能顺利完成，将带来 对阿尔茨海默病患者对调节胆管反应因素的认识有显著的积极影响 为开发ALD的新治疗方法奠定基础。