Myeloid-specific IRE1alpha as a mediator of nonalcoholic fatty liver disease

骨髓特异性 IRE1α 作为非酒精性脂肪肝疾病的介质

• 批准号: 10390111
• 负责人: William Reid Bolus
• 金额: $ 7.17万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10390111
• 关键词: Affect; American; Apoptosis; Biomedical Research; Bolus Infusion; Caliber; Cells; Cholesterol; Chronic; Cicatrix; Clinical; Coupled; Cre-LoxP; Data; Development; Diet; Elements; Endoplasmic Reticulum; Endoribonucleases; Engineering; Environment; Enzymes; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Fostering; Fructose; Funding; Genetic; Goals; Grant; Health; Healthcare; Hepatic; Human; Immune; Incidence; Individual; Inflammasome; Inflammatory; Inositol; Institution; Insulin; Insulin Resistance; Knowledge; Kupffer Cells; Lead; Letters; Liver; Liver Cirrhosis; Liver Failure; Liver Fibrosis; Liver diseases; Malignant neoplasm of liver; Measures; Mediating; Mediator of activation protein; Membrane; Mentorship; Metabolic Diseases; Metabolic dysfunction; Mind; Modernization; Molecular; Mus; Myelogenous; Myeloid Cells; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Pathogenesis; Pathology; Persons; Pharmaceutical Preparations; Phospholipids; Population; Primary carcinoma of the liver cells; Process; Production; Proteins; Publishing; RNA Splicing; Reagent; Research; Research Personnel; Research Project Grants; Ribonucleases; Risk; Role; Saturated Fatty Acids; Severity of illness; Signal Transduction; Testing; Therapeutic; Tissues; Training; Type 2 diabetic; United States National Institutes of Health; Visual; Work; Writing; XBP1 gene; base; comorbidity; cytokine; design; dietary; dietary excess; endoplasmic reticulum stress; experience; immunoregulation; improved; innovation; liver function; liver inflammation; liver transplantation; macrophage; monocyte; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; obesity treatment; prevent; recruit; response; saturated fat; sensor; skills; sugar; tool; western diet

PROJECT SUMMARY/ABSTRACT Alongside the unabating global obesity crisis, there has been a rise in non-alcoholic fatty liver disease (NAFLD), now affecting as many as ~1-in-3 Americans. While fatty liver has its own impact on liver function, a greater risk to liver health is its potential to develop into nonalcoholic steatohepatitis (NASH), hepatic cirrhosis and/or hepatocellular carcinoma. There are currently no medications approved to treat NAFLD. Moreover, complications of NASH such as hepatic insulin resistance manifest long before liver failure, and NAFLD is present in ~70% of type 2 diabetics. The mechanisms by which NAFLD develops are not well defined, but chronic nutrient excess is implicated. Indeed, mice fed high fat/sugar diets replicates many NAFLD pathologies. In particular, so called “Western” diets high in saturated fatty acids (SFA) induce endoplasmic reticulum (ER) stress in the liver, as well as activation & accumulation of hepatic myeloid cells (MCs). These MCs are key drivers of NAFLD, as grossly depleting them reduces disease severity in mice. Our lab showed excess dietary SFAs activate the ER sensor IRE1alpha (IRE1a) in MCs, and that this is necessary for SFAs to activate the NLRP3- inflammasome. This is important given that the NLRP3 inflammasome, a key inflammatory apparatus that produces IL-1beta, is an ongoing target for amelioration of obesity-associated metabolic diseases. Moreover, we found SFAs activate IRE1a via their flux into cellular phospholipids, suggesting IRE1a not only senses unfolded proteins (canonical ER stress), but also ER membrane saturation. Thus, it is remarkable the potentially important role of MC-specific IRE1a in the pathogenesis of NAFLD & NASH remains largely unexplored. We hypothesize that, in the context of nutrient excess, MC-specific IRE1a mediates activation of the NLRP3 inflammasome within the liver in a manner essential for the progression of NAFLD. We propose to test this hypothesis, including the extent to which MC-specific IRE1a can be targeted to reverse established NASH, using highly innovative & specific new mouse models. We also aim to define the specific structural domain of IRE1a required for MCs to activate the NLRP3 inflammasome and stimulate consequent IL-1beta secretion in response to SFA excess. The proposal will be carried out at UCSF, a world leader in pioneering biomedical research to improve healthcare & expand basic scientific knowledge. UCSF conducts research of the highest caliber, evidenced by being the highest NIH-funded public academic institution. UCSF fosters a highly collaborative, cross-disciplinary research environment, features that are increasingly vital for modern biomedical research. This is leveraged in the current proposal by bringing together mentorship relevant to the liver, ER stress, & immune regulation, promoting an integrated research project with an ultimate focus on metabolic dysfunction. Finally, Dr. Bolus’ current goal is to become an independent investigator, and we have strategically designed his training plan to contain key elements tailored to achieve this. This plan includes development of presentation skills (verbal, visual, & written), local & broader scientific networking, expertise in publishing & dissemination of his research, and successful grant writing.

项目摘要/摘要 除了全球肥胖危机外，非酒精性脂肪肝疾病也有所增加 （NAFLD），现在影响到大约3英寸的美国人。虽然脂肪肝对肝功能有其自身影响，但 肝脏健康的更大风险是其发展为非酒精性脂肪性肝炎（NASH），肝硬化的潜力 和/或肝细胞癌。目前尚无批准治疗NAFLD的药物。而且， 纳什（Nash 在2型糖尿病患者中存在约70％。 NAFLD开发的机制不是很好，但是慢性 养分是暗示的。实际上，喂养高脂肪/糖饮食的小鼠复制了许多NAFLD病理。在 特别是饱和脂肪酸（SFA）的所谓“西方”饮食诱导内质网应激（ER）应激 在肝脏中，以及肝髓样细胞（MC）的激活和积累。这些MC是 NAFLD严重耗尽了它们会降低小鼠的疾病严重程度。我们的实验室表现出多余的饮食SFA 激活MC中的ER传感器IRE1Alpha（IRE1A），这对于SFA激活NLRP3-是必不可少的 炎症。鉴于NLRP3炎症体是一种关键的炎症仪，这一点很重要 产生IL-1Beta，是改善肥胖相关代谢疾病的持续靶标。而且，我们 发现SFA通过其通量激活IRE1A进入细胞磷脂，这表明IRE1A不仅感官展开 蛋白质（典型的ER应力），也是ER膜安全。那是显着重要的 MC特异性IRE1A在NAFLD＆NASH发病机理中的作用仍然很大程度上是出乎意料的。我们假设 在营养过量的情况下，MC特异性IRE1A介导了NLRP3炎症体的激活 肝脏以NAFLD进展至关重要的方式。我们建议检验这一假设，包括 使用高度创新的＆ 特定的新鼠标模型。我们还旨在定义MC所需的IRE1A的特定结构域 激活NLRP3炎性体并刺激其响应SFA超过的IL-1BETA分泌。 该提案将在UCSF进行，这是UCSF，这是一个开创性生物医学研究的世界领导者，以改善医疗保健 并扩大基本科学知识。 UCSF进行了最高口径的研究，这证明了 NIH资助的最高公共学术机构。 UCSF促进了一项高度协作的跨学科研究 环境，对现代生物医学研究至关重要的特征。这是在电流中掌握的 提案通过将与肝脏，ER压力和免疫调节相关的心态汇总在一起，促进 综合研究项目最终关注代谢功能障碍。最后，Bolus博士的当前目标是 成为独立研究者，我们已经战略性地设计了他的培训计划以遏制关键要素 量身定制以实现这一目标。该计划包括发展演示技巧（口头，视觉和书面），本地＆ 更广泛的科学网络，发表和传播其研究的专业知识以及成功的赠款写作。