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: 10624788
• 负责人: William Reid Bolus
• 金额: $ 7.61万
• 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/10624788
• 关键词: Affect; American; Apoptosis; Biomedical Research; Bolus Infusion; Caliber; Cells; Cholesterol; Chronic; Cicatrix; Clinical; Coupled; Cre-LoxP; Data; Development; Diet; Disease; Elemental Diets; 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; Infiltration; Inflammasome; Inflammatory; Inositol; Institution; Insulin Resistance; Knowledge; Kupffer Cells; Letters; Liver; Liver Cirrhosis; Liver Failure; Liver Fibrosis; Liver diseases; Macrophage; Malignant neoplasm of liver; Measures; Mediating; Mediator; Membrane; Mentorship; Metabolic Diseases; Metabolic dysfunction; 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; comorbidity; cytokine; design; dietary; dietary excess; endoplasmic reticulum stress; experience; immunoregulation; improved; innovation; liver function; liver inflammation; liver transplantation; monocyte; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; obesity treatment; prevent; recruit; response; saturated fat; sensor; skills; sugar; tool; verbal; 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.

项目总结/摘要 随着全球肥胖危机的加剧，非酒精性脂肪肝的发病率也在上升。 （NAFLD），现在影响多达三分之一的美国人。虽然脂肪肝对肝功能有自己的影响， 对肝脏健康的更大风险是其发展为非酒精性脂肪性肝炎（NASH）、肝硬化和肝硬化的可能性。 和/或肝细胞癌。目前还没有药物被批准用于治疗NAFLD。此外，委员会认为， NASH的并发症如肝胰岛素抵抗早在肝功能衰竭之前就表现出来，而NAFLD是 在约70%的2型糖尿病患者中存在。NAFLD发展的机制还没有很好的定义，但慢性 营养过剩是有牵连的。事实上，喂食高脂肪/糖饮食的小鼠复制了许多NAFLD病理。在 特别是，所谓的“西方”饮食中饱和脂肪酸（SFA）高诱导内质网（ER）应激 在肝脏中，以及肝髓样细胞（MC）的活化和积累。这些MC是 NAFLD，因为严重消耗它们会降低小鼠的疾病严重程度。我们的实验室显示过量的食物脂肪酸 激活MC中的ER传感器IRE 1alpha（IRE 1a），这是SFA激活NLRP 3所必需的。 炎性小体这一点很重要，因为NLRP 3炎性小体是一种关键的炎症装置， 产生IL-1 β，是改善肥胖相关代谢疾病的持续目标。而且我们 发现SFAs通过流入细胞磷脂激活IRE 1a，表明IRE 1a不仅能感知未折叠的 蛋白质（典型的ER应激），而且ER膜饱和。因此，值得注意的是， MC-特异性IRE 1a在NAFLD和NASH发病机制中的作用仍在很大程度上未被探索。我们假设 在营养过剩的情况下，MC特异性IRE 1a介导NLRP 3炎性小体的激活， 肝脏以一种对NAFLD进展至关重要的方式。我们建议测试这个假设，包括 MC特异性IRE 1a可以靶向逆转已建立的NASH的程度，使用高度创新的 新的小鼠模型我们还旨在确定MC所需的IRE 1a的特定结构域， 激活NLRP 3炎性体并刺激随后的IL-1 β分泌以响应SFA过量。 该提案将在UCSF进行，UCSF是世界领先的生物医学研究，以改善医疗保健 扩大基础科学知识。UCSF进行最高水平的研究，证明是 美国国立卫生研究院资助的最高公共学术机构。UCSF促进高度协作，跨学科的研究 环境，功能是越来越重要的现代生物医学研究。这是在当前的杠杆作用 通过汇集与肝脏，ER压力和免疫调节相关的导师，促进 综合研究项目，最终重点是代谢功能障碍。最后，Bolus博士目前的目标是 成为一名独立调查员，我们从战略上设计了他的培训计划， 为实现这一目标而量身定制。该计划包括表达技能（口头、视觉和书面）、本地和 更广泛的科学网络，在出版和传播他的研究的专业知识，和成功的赠款写作。