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

项目摘要/摘要 在全球肥胖危机有增无减的同时，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，但 对肝脏健康更大的风险是它有可能发展为非酒精性脂肪性肝炎(NASH)，即肝硬变 和/或肝细胞癌。目前还没有被批准用于治疗NAFLD的药物。此外， NASH的并发症，如肝脏胰岛素抵抗，在肝功能衰竭之前很久就会出现，而NAFLD是 在约70%的2型糖尿病患者中存在。非酒精性脂肪肝的发病机制没有明确的定义，但是慢性的。 营养过剩是有牵连的。事实上，喂食高脂肪/高糖饮食的小鼠复制了许多NAFLD的病理。在……里面 特别是所谓的“西式”饮食，高饱和脂肪酸(SFA)会导致内质网(ER)应激 在肝脏中，以及肝脏髓系细胞(MC)的激活和积聚。这些MC是 NAFLD，因为大量消耗它们可以降低小鼠的疾病严重程度。我们的实验室显示膳食中的SFA超标 激活MC中的ER传感器IRE1pha(IRE1a)，这是SFA激活NLRP3-所必需的。 炎症者。这一点很重要，因为NLRP3炎症体，一个关键的炎症机构， 产生IL-1β，是改善肥胖相关代谢性疾病的持续靶点。此外，我们 发现SFA通过它们进入细胞磷脂的通量激活IRE1a，这表明IRE1a不仅仅是感觉未折叠 蛋白质(典型的内质网应激)，但也是ER膜饱和。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尚不清楚。我们假设 在营养过剩的情况下，MC特异性的IRE1a介导了NLRP3炎症体的激活 肝脏对非酒精性脂肪肝的进展至关重要。我们建议检验这一假设，包括 特定于MC的IRE1a可以在多大程度上针对现有的NASH，使用高度创新的 特定的新鼠标型号。我们还旨在定义MCs所需的IRE1a的特定结构域 激活NLRP3炎症体，刺激随后的IL-1β分泌，以回应SFA过量。 这项提案将在加州大学旧金山分校实施，该公司是生物医学研究的先驱，以改善医疗保健 拓展基础科学知识(&W)。加州大学旧金山分校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立学术机构。加州大学旧金山分校培养高度协作的跨学科研究 环境，这些特征对现代生物医学研究越来越重要。这在当前的 建议将与肝脏、内质网应激和免疫调节相关的指导结合在一起，促进 以代谢功能障碍为最终焦点的综合研究项目。最后，博卢斯博士目前的目标是 成为一名独立的调查员，我们已经战略性地设计了他的培训计划，以包含关键要素 为实现这一目标而量身定做。该计划包括发展演示技能(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方面的专业知识，以及成功的拨款申请。

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.