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Pathobiology of Liver Injury

肝损伤的病理学

基本信息

批准号：
10683101
负责人：
Harmeet Malhi
金额：
$ 42.19万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
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/10683101
关键词：
Acetylation Address 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 acid glycerol esters Generations Genetic Transcription Goals Grant Hepatocyte Histone Acetylation Histones Immune In Vitro Inflammation Inflammatory Inositol Interruption Knock-out Kupffer Cells Leukocytes Link Lipids Liver Lysine Macrophage Mediating Mediator Molecular Mouse Strains Mus Obesity Pathogenesis Pattern Persons Play Process Proteomics Research Role S100A11 gene Signal Transduction Sorting Stress Testing Transplantation United States Up-Regulation activation product biological adaptation to stress career cell injury chronic liver disease druggable target endoplasmic reticulum stress experimental study extracellular vesicles fatty liver disease genetic approach granulocyte histone acetyltransferase in vitro Model in vivo Model inhibitor insight intrahepatic liver inflammation liver injury monocyte mortality nonalcoholic steatohepatitis novel particle pharmacologic receptor receptor expression receptor for advanced glycation endproducts recruit therapeutic target transcription factor vesicular release

项目摘要

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定义肝脏炎症的机制非酒精性脂肪性肝炎（NASH）是美国最常见的慢性肝病。 NASH 的特点是内质网 (ER) 应激，导致促炎物质释放来自脂质超载（脂毒性）肝细胞的细胞外囊泡（EV）。招募的贡献单核细胞源性巨噬细胞 (MDM) 到肝内巨噬细胞 (IHM) 库的增加导致 NASH 和招募的 MDM 在炎症中发挥着关键作用。当前的提案审查了机械联系肝细胞来源的 EV 和特定 MDM 子集之间的关系。在初步研究中我们已经确定脂毒性内质网应激激活核糖核酸内切酶、肌醇需要酶 1 α (IRE1α) 的激活和其靶转录因子 X-box 结合蛋白 1 (XBP1) 上调 S100A11 的表达。这 S100A11 的上调与增强子区域的组蛋白 3 赖氨酸 27 乙酰化激活相关 S100A11的。脂毒性肝细胞释放含有 EV 的 S100A11 (S100A11-EV)。 S100A11-EV 激活晚期糖基化终产物 (RAGE) 信号传导的巨噬细胞受体。肝细胞表达 NASH 中 RAGE 的 S100A11 和 MDM 表达上调。沉默 S100A11 会降低 MDM- NASH 相关的肝脏炎症。根据这些原始初步数据，我们制定了中心假设是脂毒性肝细胞释放 S100A11-EV，激活一部分表达促炎性 RAGE 的 IHM 促进 NASH 发病机制。因此，本次活动的目标建议要了解： i) S100A11-EVs 是如何由肝细胞释放的； ii) RAGE 如何被激活巨噬细胞亚群中的脂毒性 EV； iii) 能否通过抑制来减轻肝脏炎症 S100A11-EV-RAGE 信号传输？拟议的实验将采用互补的体外和体内脂毒性和 NASH 模型，以及解决三个问题的药理学、分子和遗传学方法综合假设。首先我们将直接检验脂毒性肝细胞释放S100A11-的假设 EVs a) 由 XBP1 通过结合和招募组蛋白乙酰化驱动 S100A11 转录上调 b) 通过将 S100A11 选择性货物分选成脂毒性 EV。其次我们将直接检验 RAGE 在巨噬细胞子集中被脂毒性 EV 激活的假设 a) 产生具有多价信号活性的 RAGE 寡聚体，并且 b) 导致 RAGE 寡聚体子集的积累肝脏中表达促炎性 RAGE 的巨噬细胞。第三，我们将直接检验假设中断 S100A11-EV 诱导的 RAGE 激活可通过减少 NASH 的释放来减轻小鼠 NASH a) S100A11-EVs，和b)当巨噬细胞RAGE被删除时。此 R01 拨款申请将产生机械深入了解 NASH 中肝细胞与巨噬细胞的串扰，从而确定潜在的可药物靶标，例如 S100A11 或 RAGE 抑制剂。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Nanoparticle-Enabled Multiplexed Electrochemical Immunoassay for Detection of Surface Proteins on Extracellular Vesicles.

DOI：
10.1021/acsami.1c14506
发表时间：
2021-10
期刊：
ACS applied materials & interfaces
影响因子：
9.5
作者：
Seonhwa Lee;B. Crulhas;S. Šuvakov;S. Verkhoturov;D. Verkhoturov;M. Eller;H. Malhi;V. Garovic;E. Schweikert;Gulnaz Stybayeva;A. Revzin
通讯作者：
Seonhwa Lee;B. Crulhas;S. Šuvakov;S. Verkhoturov;D. Verkhoturov;M. Eller;H. Malhi;V. Garovic;E. Schweikert;Gulnaz Stybayeva;A. Revzin

Assessment of Lipotoxic Endoplasmic Reticulum (ER) Stress in Nonalcoholic Steatohepatitis (NASH).