Pathobiology of Liver Injury

肝损伤的病理学

• 批准号: 10292719
• 负责人: Harmeet Malhi
• 金额: $ 40.99万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-23 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10292719
• 关键词: Acetylation; Address; Americas; Applications Grants; Attenuated; Binding; Binding Proteins; Cell Communication; Cell Line; Cells; Communication; Complex; Data; Diet; Disease; Disease Progression; EP300 gene; Economic Burden; Endoribonucleases; Enhancers; Enzymes; Epigenetic Process; Factor X; Fatty Liver; Fatty acid glycerol esters; Generations; Genetic Transcription; Goals; Grant; Hepatic; Hepatocyte; Histones; Immune; In Vitro; Inflammation; Inflammatory; Inositol; Interruption; Knock-out; Kupffer Cells; Leukocytes; Link; Lipids; Liver; Liver diseases; Lysine; Mediating; Mediator of activation protein; Molecular; Molecular Genetics; Mouse Strains; Mus; Obesity; Pathogenesis; Pattern; Pharmacology; Play; Process; Proteomics; Research; Role; S100A11 gene; Signal Transduction; Sorting - Cell Movement; Stress; Testing; Transplantation; United States; Up-Regulation; base; biological adaptation to stress; career; cell injury; chronic liver disease; druggable target; endoplasmic reticulum stress; experimental study; extracellular vesicles; genetic approach; granulocyte; in vitro Model; in vivo Model; inhibitor/antagonist; insight; intrahepatic; liver inflammation; liver injury; macrophage; monocyte; mortality; nonalcoholic steatohepatitis; novel; particle; receptor; receptor expression; receptor for advanced glycation endproducts; recruit; therapeutic target; transcription factor; vesicular release

PROJECT ABSTRACT. My long term career objective is to define the mechanisms of liver inflammation in nonalcoholic steatohepatitis (NASH), the most-prevalent chronic liver disease in the United States of America. NASH is characterized by endoplasmic reticulum (ER) stress, which results in release of proinflammatory extracellular vesicles (EVs) from lipid overloaded (lipotoxic) hepatocytes. The contribution of recruited monocyte-derived macrophages (MDMs) to the intrahepatic macrophage (IHM) pool increases in NASH and the recruited MDMs play a pivotal role in inflammation. The current proposal examines the mechanistic link between hepatocyte-derived EVs and specific MDM subsets. In preliminary studies we have identified that activation of the lipotoxic ER stress activated endoribonuclease, inositol requiring enzyme 1 alpha (IRE1α) and its target transcription factor X-box binding protein 1 (XBP1), upregulates the expression of S100A11. This upregulation of S100A11 is associated with activating, histone 3 lysine 27, acetylation in the enhancer region of S100A11. Lipotoxic hepatocytes release S100A11 containing EVs (S100A11-EVs). S100A11-EVs activate macrophage receptor for advanced glycation endproducts (RAGE) signaling. Hepatocellular expression of S100A11 and MDM expression of RAGE are upregulated in NASH. Silencing S100A11 decreases MDM- associated hepatic inflammation in NASH. Based on these original preliminary data, we have formulated the CENTRAL HYPOTHESIS that lipotoxic hepatocytes release S100A11-EVs which activate a subset of proinflammatory RAGE expressing IHMs promoting NASH pathogenesis. Therefore, the goals of this proposal are to understand: i) how S100A11-EVs are released by hepatocytes; ii) how RAGE is activated by lipotoxic EVs in a subset of macrophages; and iii) can hepatic inflammation be attenuated by inhibiting S100A11-EV-RAGE signaling? The proposed experiments will employ complementary in vitro and in vivo models of lipotoxicity and NASH, and pharmacological, molecular and genetic approaches to address three integrated hypotheses. First we will directly test the hypothesis that lipotoxic hepatocytes release S100A11- EVs a) by XBP1 driven transcriptional upregulation of S100A11 by binding to and recruiting histone acetylating factors to an enhancer region, and b) by selective cargo sorting of S100A11 into lipotoxic EVs. Second we will directly test the hypothesis that RAGE is activated in a subset of macrophages by lipotoxic EVs a) by generating multivalent signal competent RAGE oligomers, and b) leads to the accumulation of a subset of proinflammatory RAGE expressing macrophages in the liver. Third we will directly test the hypothesis that interrupting S100A11-EV induced RAGE activation attenuates murine NASH a) by reducing the release of S100A11-EVs, and b) when macrophage RAGE is deleted. This R01 grant application will yield mechanistic insights into hepatocyte-to-macrophage crosstalk in NASH, thus identifying potentially druggable targets, e.g., inhibitors of S100A11 or RAGE.

项目摘要。我的长期职业目标是确定肝脏炎症的机制