Liver-enriched Transcription Factors as Prognostic Markers and Therapeutic Targets in Alcoholic Hepatitis

肝脏富集转录因子作为酒精性肝炎的预后标志物和治疗靶点

• 批准号: 10428560
• 负责人: Gavin E Arteel
• 金额: $ 24.1万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-22 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10428560
• 关键词: Alcoholic Hepatitis; Alcoholic Liver Diseases; Area; Biological Markers; CSF3 gene; Cell Differentiation process; Cells; Clinical; Clinical Data; Coupled; DNA Binding; Data; Development; Disease; Down-Regulation; EGF gene; Enrollment; Epidermal Growth Factor Receptor; Failure; Functional disorder; Genes; Glycoproteins; Goals; HNF4A gene; Hepatobiliary; Hepatocyte; Human; Immunoprecipitation; In Vitro; Inflammation; Inflammatory; Knowledge; Lead; Ligands; Link; Liver; Liver Fibrosis; Mass Spectrum Analysis; Mediating; Microdissection; Molecular; Natural regeneration; Neutrophil Infiltration; Organoids; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Peripheral; Phenotype; Play; Post Translational Modification Analysis; Prognostic Marker; Protein Isoforms; Proteins; Proteome; Proteomics; Reaction; Regenerative response; Regulation; Reporter; Research; Role; Sampling; Serum; Serum Proteins; Severities; Severity of illness; Signal Transduction; System; Techniques; Therapeutic; Tissues; base; cohort; effective therapy; experimental study; genetic signature; genomic profiles; in vitro Model; innovation; liver function; mortality; novel; novel therapeutic intervention; novel therapeutics; precision medicine; prednisolone; premature; preservation; promoter; protein biomarkers; response; screening; standard of care; stem cells; targeted treatment; therapeutic target; tool; transcription factor; transcriptome; transcriptome sequencing; transcriptomics; treatment response

Bataller – UO1 (RFA AA-18-003) ABSTRACT Hepatocellular failure is a hallmark finding in patients with alcoholic hepatitis (AH). Current therapy is not fully effective and targeted therapies are needed. Most research has been focused on the role of inflammation. In contrast, the mechanisms underlying hepatocellular failure and the subsequent poor regenerative response in AH are unknown. Our group showed that severe AH is characterized by a massive, yet inefficient accumulation of ductular cells. The central aim of this proposal is to identify the molecular mechanisms underlying the hepatocellular failure and the subsequent poor regenerative response in AH. The ultimate goal is the identification of prognostic markers and therapeutic targets useful for precision medicine. We have generated strong preliminary data in human livers showing: (1) progression of early forms of ALD to AH is characterized by a profound decrease in the function of HNF4A. (2) HNF4A network footprint closely correlates with disease severity in AH patients. (3) TGFβ1 and EGF are key upstream modulators in AH and regulate LETF in cultured human hepatocytes. (4) The gene signature of the ductular reaction in AH shows enriched inflammatory, fibrogenic and proliferative signals and decreased HNF4A activity. And (5) Secreted proteins encoded by LEFT-target genes are detected in sera of patients with AH. Based on these strong preliminary data, our specific aims are (1) To uncover the molecular mechanism of HNF4A isoform regulation by TGFβ1, by characterizing the interactome of the HNF4A P1 dependent isoforms by MS coupled Immunoprecipitation. Moreover, we aim at identifying the DNA binding regions of HNF4A P2 isoform by ChIPseq, and generating a promoter reporter system that will be used for in vitro high- troughput screening of novel drugs. (2) To investigate the relevance and genomic profile of ductular proliferation and de-differentiated hepatocytes in AH by means of RNAseq of microdissected areas and correlation of gene signatures with clinical outcome. We have developed human organoids of ductular reaction that represents a novel tool to study the effect of TGFβ1 and EGFR ligands in HNF4A. And (3). To identify new serum protein biomarkers of AH by investigating serum N-linked glycoprotein compartment by glycoprotein selection coupled to MS and by analyzing post-translational modifications of the serum proteome by Snap-shot proteomic array. We will combine analysis of serum proteomic data with transcriptomic studies of total and microdissected liver tissue and correlate the resulting signatures with clinical outcomes including mortality and response to prednisolone and G-CSF.

巴特勒 – UO1 (RFA AA-18-003) 抽象的 肝细胞衰竭是酒精性肝炎 (AH) 患者当前治疗的一个标志性发现。 并不完全有效，需要进行靶向治疗。 相反，肝细胞衰竭的机制和 AH 的后续不良再生反应尚不清楚，我们的研究小组表明，严重的 AH 会导致严重的再生反应。 其特点是导管细胞大量但低效的积累。 该提案旨在确定肝细胞衰竭的分子机制和 AH 中随后的不良再生反应的最终目标是确定预后。 我们已经产生了对精准医学有用的标记物和治疗靶点。 人类肝脏的初步数据显示：(1) 早期形式的 ALD 进展为 AH (2) HNF4A网络足迹 (3) TGFβ1和EGF是关键上游 AH 中的调节剂并调节培养的人肝细胞中的 LETF (4) 的基因特征。 AH 中的导管反应显示出丰富的炎症、纤维化和增殖信号， (5) LEFT-靶基因编码的分泌蛋白被降低。 在 AH 患者的血清中检测到基于这些强有力的初步数据，我们的具体目标是 (1) 揭示TGFβ1调控HNF4A亚型的分子机制，通过 通过 MS 耦合表征 HNF4A P1 依赖亚型的相互作用组 此外，我们的目标是鉴定 HNF4A P2 的 DNA 结合区域。 通过 ChIPseq 进行同工型，并生成启动子报告系统，用于体外高 (2) 研究相关性和基因组谱 通过 RNAseq 观察 AH 中的导管增殖和去分化肝细胞 我们有显微解剖区域以及基因特征与临床结果的相关性。 开发了导管反应的人类类器官，它代表了一种研究效应的新工具 (3) 鉴定 HNF4A 中的 TGFβ1 和 EGFR 配体。 AH 通过糖蛋白选择耦合研究血清 N 连接糖蛋白区室 到 MS 并通过 Snap-shot 分析血清蛋白质组的翻译后修饰 我们将把血清蛋白质组数据分析与转录组研究结合起来。 总肝组织和显微解剖肝组织，并将所得特征与临床结果相关联 包括死亡率和对泼尼松龙和 G-CSF 的反应。

项目成果

The outcome of boosting mitochondrial activity in alcohol-associated liver disease is organ-dependent.

• DOI: 10.1097/hep.0000000000000303
• 发表时间: 2023-09-01
• 期刊: HEPATOLOGY
• 影响因子: 13.5
• 作者: Goikoetxea-Usandizaga, Naroa;Bravo, Miren;Egia-Mendikute, Leire;Abecia, Leticia;Serrano-Macia, Marina;Urdinguio, Rocio G.;Clos-Garcia, Marc;Rodriguez-Agudo, Ruben;Araujo-Legido, Raquel;Lopez-Bermudo, Lucia;Delgado, Teresa C.;Lachiondo-Ortega, Sofia;Gonzalez-Recio, Irene;Gil-Pitarch, Claudia;Pena-Cearra, Ainize;Simon, Jorge;Benede-Ubieto, Raquel;Arino, Silvia;Herranz, Jose M.;Azkargorta, Mikel;Salazar-Bermeo, Julio;Marti, Nuria;Varela-Rey, Marta;Falcon-Perez, Juan M.;Lorenzo, Oscar;Nogueiras, Ruben;Elortza, Felix;Nevzorova, Yulia A.;Cubero, Francisco J.;Saura, Domingo;Martinez-Cruz, Luis Alfonso;Sabio, Guadalupe;Palazon, Asis;Sancho-Bru, Pau;Elguezabal, Natalia;Fraga, Mario F.;Avila, Matias A.;Bataller, Ramon;Marin, Jose J. G.;Martin, Franz;Martinez-Chantar, Maria Luz
• 通讯作者: Martinez-Chantar, Maria Luz

Ductular reaction promotes intrahepatic angiogenesis through Slit2-Roundabout 1 signaling.

• DOI: 10.1002/hep.32140
• 发表时间: 2022-03
• 期刊: Hepatology (Baltimore, Md.)
• 作者: Coll M;Ariño S;Martínez-Sánchez C;Garcia-Pras E;Gallego J;Moles A;Aguilar-Bravo B;Blaya D;Vallverdú J;Rubio-Tomás T;Lozano JJ;Pose E;Graupera I;Fernández-Vidal A;Pol A;Bataller R;Geng JG;Ginès P;Fernandez M;Sancho-Bru P
• 通讯作者: Sancho-Bru P