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Blocking hepatocyte senescence as a novel therapeutic strategy for chronic liver diseases

阻断肝细胞衰老作为慢性肝病的新治疗策略

基本信息

批准号：
10686416
负责人：
Michael Oertel
金额：
$ 61.62万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10686416
关键词：
Alcoholic Liver Diseases Animal Model Automobile Driving Cell Aging Cell Cycle Arrest Cells Chemicals Cirrhosis Clinical Confocal Microscopy DNA Damage Data Disease Progression Fibrosis Functional disorder Genes Growth Growth Factor Health Hepatic Hepatocyte Hepatocyte transplantation Human Immune Immunology Impairment In Vitro Inflammation Investigation Knowledge Ligation Light Liver Liver Cirrhosis Liver Dysfunction Liver Fibrosis Liver diseases Mediating Mediator Metabolic Modeling Molecular Mus Oncogene Activation Paracrine Communication Pathogenesis Pathology Patients Peptide Hydrolases Phenotype Play Population Publishing Rattus Reporting Reproducibility Rodent Rodent Model Role Stimulus System Testing Therapeutic Thioacetamide Tissues activin A antagonist autocrine beta-Galactosidase bile duct chemokine chronic liver disease clinically relevant comparative cytokine experience experimental study immune cell infiltrate in vivo inhibitor insight laser capture microdissection liver inflammation liver injury liver transplantation mouse model non-alcoholic fatty liver disease novel novel therapeutic intervention overexpression paracrine permissiveness prevent response senescence telomere transcriptome sequencing transplant model vector induced

项目摘要

Summary: There is growing evidence implicating that cellular senescence is involved in the progression of chronic liver diseases (CLD). However, the mechanisms underpinning cellular senescence-mediated progression of CLD remain unclear. We have recently reported an important role of the activin A/p15INK4b axis in inducing hepatocyte (HC) senescence. Further suggesting a role of the activin A/p15INK4b axis in inducing HC senescence in CLD, because our preliminary data from rat models of liver cirrhosis revealed increased activin A and p15INK4b expression in cirrhotic liver tissue regions, which correlated with increased hepatic SA-β-gal activity. We also found that elevated p15INK4b expression in the livers of mice treated with CCl4 and observed that activin A inhibition markedly reduced CCl4-induced hepatic injury. Increased levels of activin A are also reported in several human CLDs, and our preliminary data demonstrate increased activin A expression in the livers of cirrhosis patients. Based on this evidence, we hypothesized that activin A contributes to the pathogenesis of CLDs by driving p15INK4b-mediated induction of HC senescence. Senescence-associated secretory phenotype (SASP) factors produced by senescent HCs promote inflammation and fibrosis, resulting in CLD progression. We will test our hypothesis using our established rat HC transplantation model and rodent models of CLD according to the following integrated Specific Aims. In Aim 1, we will use our HC-transplantation model to precisely demarcate senescent and neighboring cells, followed by isolation of both cell populations using laser-capture microdissection (LCM). Comparative analyses of these foci and their surrounding regions will reveal paracrine signals from senescent HCs and their phenotypic effects on neighboring HCs. Aim 2 will investigate the effect of activin A/p15INK4b-induced HC senescence in both rat and mouse models of CLD. Studies in the mouse model will also include a comprehensive phenotypic and functional analysis of hepatic immune cell infiltrates to determine the impact of HC senescence on immune cells. We will also evaluate hepatic expression of activin A and p15INK4b in cirrhotic patients by confocal microscopy to determine the clinical relevance of the activin A/p15INK4b axis. Lastly, in Aim 3, we will investigate the therapeutic benefit of targeting senescence in CLDs. This application leverages our combined expertise in liver transplantation models (Oertel, MPI), animal models of liver diseases (Oertel/Raeman, MPIs), immunology (Raeman), and senescence (Oertel), as well as extensive experience in hepato-pathology and RNA-seq analyses (Locker, Co-I) and lentiviral/AAV expression systems (Bell, Co-I), to investigate the mechanisms underpinning HC senescence and the role of senescent HCs and their detrimental effects on neighboring cells in the pathogenesis of CLD. The results of our investigations will lead to identification of therapeutic strategies to prevent or halt progression of CLD by targeting hepatic senescence.

总结：越来越多的证据表明，细胞衰老参与了慢性肝病的进展，疾病（CLD）。然而，细胞衰老介导的CLD进展的基础机制仍然不清楚。我们最近报道了激活素A/p15 INK 4 b轴在诱导细胞凋亡中的重要作用。肝细胞（HC）衰老。进一步表明激活素A/p15 INK 4 b轴在诱导HC中的作用 CLD中的衰老，因为我们从肝硬化大鼠模型的初步数据显示，激活素A和p15 INK 4 b在肝硬化组织区域的表达，与肝硬化患者肝组织中激活素A和p15 INK 4 b的表达增加相关。 SA-β-gal活性。我们还发现，在用CCl 4处理的小鼠肝脏中，p15 INK 4 b表达升高，观察到激活素A抑制显著减少CCl 4诱导的肝损伤。激活素水平升高在几种人类CLD中也有报道，我们的初步数据表明激活素A的增加在肝硬化患者的肝脏中表达。基于这些证据，我们假设激活素A 通过驱动p15 INK 4 b介导的HC衰老诱导而促成CLD的发病机制。衰老HC产生的衰老相关分泌表型（SASP）因子促进炎症和纤维化，导致CLD进展。我们将使用我们的建立大鼠HC移植模型和啮齿类CLD模型具体目标。在目标1中，我们将使用我们的HC移植模型来精确地区分衰老和相邻细胞，随后使用激光捕获显微切割（LCM）分离两个细胞群体。对这些病灶及其周围区域的比较分析，将揭示出衰老的HC及其对邻近HC的表型效应。目的2：研究激活素 A/p15 INK 4 b在CLD大鼠和小鼠模型中诱导HC衰老。小鼠模型的研究将还包括肝脏免疫细胞浸润的综合表型和功能分析，确定HC衰老对免疫细胞的影响。我们还将评估肝脏中激活素A和p15 INK 4 b的临床意义，激活素A/p15 INK 4 b轴。最后，在目标3中，我们将研究靶向衰老的治疗益处， CLDs。该应用程序利用了我们在肝移植模型（Oertel，MPI）方面的综合专业知识，肝脏疾病（Oertel/Raeman，MPI）、免疫学（Raeman）和衰老（Oertel）的动物模型，以及在肝脏病理学和RNA测序分析方面的丰富经验（Locker，Co-I），慢病毒/AAV表达系统（Bell，Co-I），以研究支持HC衰老的机制以及衰老的毛细胞的作用及其对邻近细胞的有害影响， CLD。我们的调查结果将导致确定治疗策略，以防止或停止通过靶向肝衰老来控制CLD的进展。