Hepatic TrkB-T1 signaling in NASH pathogenesis and resolution

NASH 发病机制和解决方案中的肝脏 TrkB-T1 信号传导

• 批准号: 10675970
• 负责人: Jiandie D Lin
• 金额: $ 57.87万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 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 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10675970
• 关键词: Ablation; Address; Automobile Driving; Binding; Biology; Brain-Derived Neurotrophic Factor; Cell Death; Cells; Chimeric Proteins; Data; Diet; Disease; Disease Progression; Disease model; Fatty Liver; Fibrosis; Functional disorder; Future; Genetic Models; Hepatic; Hepatocyte; Heterogeneity; Human; Inflammation; Injury; Knockout Mice; Knowledge; Length; Ligands; Link; Liver; Liver diseases; Mediating; Metabolic; Metabolic Diseases; Metabolic stress; Modeling; Molecular; Mus; NF-kappa B; Nature; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Phosphotransferases; Protein Isoforms; Proteins; Recombinants; Resolution; Role; Shapes; Signal Pathway; Signal Transduction; Stress; Testing; Therapeutic; Translational Research; Treatment Efficacy; Tropomyosin; Work; cell type; design; effective therapy; efficacy evaluation; fatty liver disease; feeding; genomic tools; hepatocyte injury; improved; insight; intrahepatic; liver injury; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel therapeutics; overexpression; pre-clinical; protective effect; receptor; therapeutic development; tool; transcriptome sequencing; transcriptomics

Project Summary/Abstract Nonalcoholic steatohepatitis (NASH) is a progressive metabolic liver disease characterized by persistent liver injury, inflammation, and fibrosis. Reprogramming of intrahepatic signaling and liver microenvironment is a hallmark of NASH pathogenesis in mice and humans. However, the molecular nature of pathophysiological signaling that drives NASH progression remains an important unsolved question. To address this critical knowledge gap, we performed bulk and single-cell transcriptomic analysis on healthy and diet-induced NASH mouse livers. Our work revealed several transcriptomic signatures of NASH, liver cell heterogeneity and reprogramming during disease pathogenesis, and the landscape of intercellular crosstalk in the liver. Importantly, key features of NASH-associated reprogramming of the liver microenvironment and intrahepatic signaling in mice are notably conserved in human NASH. Hepatocytes respond to metabolic stresses in NASH by engaging adaptive and maladaptive signaling pathways that ultimately lead to liver steatosis and hepatocyte injury. In preliminary studies, we observed that hepatic expression of the truncated isoform of Tropomyosin receptor kinase B (TrkB), TrkB-T1, but not the full-length TrkB isoform, was selectively and markedly upregulated in mouse and human NASH. However, whether and how aberrant activation of hepatic TrkB-T1 signaling contributes to NASH pathogenesis has not been explored. Based on a body of preliminary data, we hypothesize that pathogenic activation of TrkB-T1 signaling sensitizes hepatocytes to stress-induced injury. In this proposal, we plan to investigate the role of TrkB-T1 in liver injury and NASH progression. We will explore cell-intrinsic and extrinsic mechanisms that mediate the effects of TrkB-T1 on NASH pathogenesis. Finally, we will explore the therapeutic potential of targeting this pathway for NASH treatment. Successful completion of this project will provide novel insights into the pathophysiology of NASH and generate critical preclinical data that will guide future translational work.

项目概要/摘要 非酒精性脂肪性肝炎（NASH）是一种进行性代谢性肝病，其特征是持续性肝病 损伤、炎症和纤维化。肝内信号传导和肝脏微环境的重新编程是 小鼠和人类 NASH 发病机制的标志。然而，病理生理学的分子性质 驱动 NASH 进展的信号仍然是一个尚未解决的重要问题。为了解决这个关键问题 为了弥补知识差距，我们对健康和饮食引起的 NASH 进行了批量和单细胞转录组分析 小鼠肝脏。我们的工作揭示了 NASH、肝细胞异质性和 疾病发病机制中的重编程以及肝脏中细胞间串扰的景观。 重要的是，NASH 相关的肝脏微环境和肝内重编程的关键特征 小鼠体内的信号传导在人类 NASH 中尤其保守。肝细胞对 NASH 代谢应激做出反应 通过参与适应性和适应不良信号通路，最终导致肝脏脂肪变性和肝细胞 受伤。在初步研究中，我们观察到原肌球蛋白截短亚型的肝脏表达 受体激酶 B (TrkB)、TrkB-T1，但不是全长 TrkB 亚型，选择性且显着地 在小鼠和人类 NASH 中上调。然而，肝脏 TrkB-T1 是否以及如何异常激活 信号传导对 NASH 发病机制的影响尚未得到探索。根据大量初步数据，我们 假设 TrkB-T1 信号的致病激活使肝细胞对应激诱导的损伤敏感。在 根据该提案，我们计划研究 TrkB-T1 在肝损伤和 NASH 进展中的作用。我们将探索 介导 TrkB-T1 对 NASH 发病机制影响的细胞内在和外在机制。最后，我们 将探索针对 NASH 治疗的这一途径的治疗潜力。顺利完成 该项目将为 NASH 的病理生理学提供新的见解并生成关键的临床前数据 这将指导未来的翻译工作。