Elucidating the role of the FXR-PTEN-PI3K-AKT-mTOR axis in liver progenitor cell-driven liver regeneration

阐明 FXR-PTEN-PI3K-AKT-mTOR 轴在肝祖细胞驱动的肝再生中的作用

• 批准号: 10620261
• 负责人: Donghun Shin
• 金额: $ 51.09万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-25 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10620261
• 关键词: Ablation; Agonist; Animals; Applications Grants; Biliary; Bone Morphogenetic Proteins; Bromodomain; Cell Count; Cell Survival; Cell secretion; Chemicals; Clinical Trials; Data; Defect; Disease; Epithelial Cells; FRAP1 gene; Fatty Liver; Fibrosis; Genes; Genetic; Goals; Grant; Hepatic Mass; Hepatocyte; Impairment; Inflammation; Inflammatory; Investigation; Larva; Liver; Liver Regeneration; Liver diseases; Mammals; Modeling; Molecular; Morbidity - disease rate; Mus; Natural regeneration; Necrosis; Nuclear Receptors; Optics; PIK3CG gene; PTEN gene; Pathway interactions; Patients; Persons; Phase; Process; Proteins; Proto-Oncogene Proteins c-akt; Publishing; Reaction; Receptor Activation; Receptor Signaling; Recovery; Repression; Role; Severity of illness; Signaling Protein; Testing; Therapeutic; Work; Zebrafish; antagonist; chronic liver disease; cytokine; effective therapy; end stage liver disease; farnesoid X-activated receptor; inhibitor; insight; liver cell proliferation; liver function; liver injury; liver repair; liver transplantation; mortality; mouse model; mutant; oval cell; pharmacologic; phosphatase of regenerating liver; receptor; regeneration model; screening; stem cell proliferation; stem cells; tool

Chronic liver diseases are among the leading causes of mortality and morbidity in the U.S., with 5.5 million people suffering from these diseases. Currently, liver transplantation is the only definitive treatment for end-stage liver diseases; however, the shortage of donor livers makes this therapy extremely limited. Augmenting innate liver regeneration in advanced liver diseases is an attractive therapeutic alternative. To develop such a therapy, it is crucial to understand the molecular mechanisms of liver regeneration, particularly in the diseased liver. Upon liver injury, hepatocytes proliferate to yield more hepatocytes to restore lost liver mass and maintain liver function. However, when hepatocyte proliferation is compromised, a phenomenon observed in advanced liver diseases, or when massive hepatocyte necrosis occurs, liver progenitor cells (LPCs) are activated and these LPCs expand and are able to differentiate into hepatocytes. A correlation between disease severity and LPC numbers in patients with chronic liver diseases suggests the occurrence of LPC activation in the diseased livers but its poor differentiation into hepatocytes. In addition, LPCs secrete pro-inflammatory, pro-fibrogenic cytokines that can perpetuate inflammation and contribute to subsequent fibrosis. Thus, augmenting innate LPC-driven liver regeneration is expected to have beneficial effects in liver patients by generating more functional hepatocytes and by concomitantly reducing inflammation and fibrosis. Despite this significance, the molecular basis of LPC- driven liver regeneration remains poorly understood. Our long-term goal is to completely delineate the molecular mechanisms underlying LPC-driven liver regeneration. In pursuit of this goal, during the previous grant cycle, we elucidated the crucial role of bone morphogenetic protein (BMP) signaling in LPC-driven liver regeneration; in this renewal grant application, we propose to determine how the nuclear receptor farnesoid X receptor (FXR) regulates LPC-driven liver regeneration. We have established both zebrafish and mouse liver injury models for LPC-driven liver regeneration. Using the zebrafish model, we performed chemical screening and discovered that treatment with a synthetic FXR agonist, GW4064, impaired LPC-driven regeneration. Given the beneficial effects of FXR agonists on hepatic steatosis, fibrosis, and hepatocyte-driven liver regeneration and the multiple clinical trials of the agonists, their negative effect on LPC-driven liver regeneration is unexpected and surprising, justifying an extensive mechanistic investigation. Based on our preliminary findings, we hypothesize that FXR activation impairs LPC-driven liver regeneration by repressing the PI3K-AKT-mTOR pathway. We will test this hypothesis by elucidating the effects of FXR activation and suppression on LPC-driven liver regeneration (Aim 1) and by determining the role of the PTEN-PI3K-AKT-mTOR axis in the regeneration process (Aim 2). Successful accomplishment of the proposed work will not only significantly advance the mechanistic understanding of liver regeneration in diseased livers, but also support a more cautionary administration of FXR agonists for treating patients with advanced liver diseases.

在美国，慢性肝病是导致死亡和发病的主要原因之一，有550万人

项目成果

Hepatocyte-to-cholangiocyte conversion occurs through transdifferentiation independently of proliferation in zebrafish.

• DOI: 10.1097/hep.0000000000000016
• 发表时间: 2023-04-01
• 期刊: HEPATOLOGY
• 影响因子: 13.5
• 作者: Lee, Seung-Hoon;So, Juhoon;Shin, Donghun
• 通讯作者: Shin, Donghun

tomm22 Knockdown-Mediated Hepatocyte Damages Elicit Both the Formation of Hybrid Hepatocytes and Biliary Conversion to Hepatocytes in Zebrafish Larvae.

tomm22 敲低介导的肝细胞损伤引起斑马鱼幼虫中混合肝细胞的形成和胆汁向肝细胞的转化。

• DOI: 10.3727/105221617x695195
• 发表时间: 2017
• 期刊: Gene expression
• 作者: Wu,Jianchen;Choi,Tae-Young;Shin,Donghun
• 通讯作者: Shin,Donghun

PPARα activation promotes liver progenitor cell-mediated liver regeneration by suppressing YAP signaling in zebrafish.

• DOI: 10.1038/s41598-023-44935-5
• 发表时间: 2023-10-25
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Kim, Minwook;So, Juhoon;Shin, Donghun
• 通讯作者: Shin, Donghun

Attenuating the Epidermal Growth Factor Receptor-Extracellular Signal-Regulated Kinase-Sex-Determining Region Y-Box 9 Axis Promotes Liver Progenitor Cell-Mediated Liver Regeneration in Zebrafish.

• DOI: 10.1002/hep.31437
• 发表时间: 2021-04
• 期刊: Hepatology (Baltimore, Md.)
• 作者: So J;Kim M;Lee SH;Ko S;Lee DA;Park H;Azuma M;Parsons MJ;Prober D;Shin D
• 通讯作者: Shin D

Biliary-Atresia-Associated Mannosidase-1-Alpha-2 Gene Regulates Biliary and Ciliary Morphogenesis and Laterality.

• DOI: 10.3389/fphys.2020.538701
• 发表时间: 2020
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: So J;Ningappa M;Glessner J;Min J;Ashokkumar C;Ranganathan S;Higgs BW;Li D;Sun Q;Schmitt L;Biery AC;Dobrowolski S;Trautz C;Fuhrman L;Schwartz MC;Klena NT;Fusco J;Prasadan K;Adenuga M;Mohamed N;Yan Q;Chen W;Horne W;Dhawan A;Sharif K;Kelly D;Squires RH;Gittes GK;Hakonarson H;Morell V;Lo C;Subramaniam S;Shin D;Sindhi R
• 通讯作者: Sindhi R