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.

项目概要/摘要 随着全球肥胖危机不断加剧，非酒精性脂肪肝发病率也有所上升 （NAFLD），现在影响了大约三分之一的美国人。虽然脂肪肝对肝功能有其自身的影响， 对肝脏健康的更大风险是其有可能发展为非酒精性脂肪性肝炎 (NASH)、肝硬化 和/或肝细胞癌。目前尚无批准用于治疗 NAFLD 的药物。而且， NASH 的并发症，例如肝胰岛素抵抗，早在肝衰竭之前就已出现，而 NAFLD 则 存在于约 70% 的 2 型糖尿病患者中。 NAFLD 的发展机制尚不明确，但属于慢性病 与营养过剩有关。事实上，喂食高脂肪/高糖饮食的小鼠会复制许多 NAFLD 病理。在 特别是，富含饱和脂肪酸（SFA）的所谓“西方”饮食会诱发内质网（ER）应激 在肝脏中，以及肝髓细胞 (MC) 的激活和积累。这些 MC 是关键驱动力 NAFLD，因为严重消耗它们可以降低小鼠疾病的严重程度。我们的实验室显示饮食中的 SFA 过量 激活 MC 中的 ER 传感器 IRE1alpha (IRE1a)，这对于 SFA 激活 NLRP3- 是必要的 炎症小体。这一点很重要，因为 NLRP3 炎症小体是一种关键的炎症装置， 产生IL-1β，是改善肥胖相关代谢疾病的持续目标。此外，我们 发现 SFA 通过流入细胞磷脂来激活 IRE1a，这表明 IRE1a 不仅能感知未折叠的 蛋白质（典型的 ER 应激），还有 ER 膜饱和度。因此，值得注意的是，潜在的重要 MC 特异性 IRE1a 在 NAFLD 和 NASH 发病机制中的作用在很大程度上仍未被探索。我们假设 在营养过剩的情况下，MC 特异性 IRE1a 介导 NLRP3 炎症小体的激活 肝脏以一种对于 NAFLD 进展至关重要的方式。我们建议检验这一假设，包括 MC 特异性 IRE1a 可以在多大程度上利用高度创新和 具体的新鼠标型号。我们还旨在定义 MC 所需的 IRE1a 的特定结构域 激活 NLRP3 炎症小体并刺激随后的 IL-1beta 分泌以响应 SFA 过量。 该提案将在加州大学旧金山分校进行，加州大学旧金山分校是改善医疗保健的生物医学研究领域的世界领先者 并扩展基础科学知识。加州大学旧金山分校 (UCSF) 开展了最高水平的研究，这证明了 NIH 资助的最高公立学术机构。加州大学旧金山分校 (UCSF) 促进高度协作、跨学科的研究 环境、特征对于现代生物医学研究越来越重要。这是当前的杠杆 通过汇集与肝脏、ER 压力和免疫调节相关的指导，促进 最终重点关注代谢功能障碍的综合研究项目。最后，Bolus 博士当前的目标是 成为一名独立调查员，我们战略性地设计了他的培训计划，其中包含关键要素 为实现这一目标而量身定制。该计划包括发展表达能力（口头、视觉和书面）、本地和 更广泛的科学网络、出版和传播其研究的专业知识以及成功的资助申请。