RAGE, DIAPH1 and IRF7 and Macrophage Dysfunction in Atherosclerosis and Cardiometabolic Disease

动脉粥样硬化和心脏代谢疾病中的 RAGE、DIAPH1 和 IRF7 以及巨噬细胞功能障碍

• 批准号: 10424906
• 负责人: ANN MARIE SCHMIDT
• 金额: $ 50.18万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10424906
• 关键词: Address; Adipocytes; Adipose tissue; Antisense Oligonucleotides; Arterial Fatty Streak; Atherosclerosis; Binding; Bone Marrow; Cardiometabolic Disease; Cell Nucleus; Cells; Cholesterol; Communication; Complex; Coupled; Cues; Cytoplasmic Tail; Databases; Diet; Encapsulated; Fat-Restricted Diet; Fatty Liver; Fibrosis; Fructose; Functional disorder; Genetic Transcription; Glucans; Glucose; Hepatic; Hepatic Stellate Cell; Hepatocyte; High Fat Diet; Home; Immune; Impairment; Inflammation; Insulin; Insulin Resistance; Kupffer Cells; Lead; Lipids; Liver; Liver Fibrosis; Maps; Mediating; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Molecular; Mus; Myelogenous; Myeloid Cells; Names; Obesity; Organ; Palmitates; Pathogenesis; Plasma; RAGE gene; Regulation; Role; Signal Pathway; Signal Transduction; Site; Stimulus; Testing; Time; Tissues; Transplantation; Triglycerides; Up-Regulation; Work; antagonist; cardiometabolism; cytokine; human tissue; interferon regulatory factor-7; lens; lipid metabolism; macrophage; nonalcoholic steatohepatitis; novel; particle; programs; receptor for advanced glycation endproducts; recruit; response; small molecule; synergism; trafficking; transcriptome; transcriptome sequencing; transcriptomics; western diet

Summary: Project 3 Our Program Project has unveiled key roles for macrophage metabolism, depot-, cue-, and time-dependent molecular re-programming and intraorgan trafficking in the pathogenesis of cardiometabolic dysfunction. In each metabolic setting, including the atherosclerotic plaque, obese adipose tissue and liver, the composition of the tissue-specific niche, such as excess lipid content, and recruitment and trafficking of infiltrating bone marrow- derived immune cells, which deliver signals to activate endogenous signaling pathways in resident immune cells (e.g., adipose tissue macrophages or liver Kupffer cells), defines the breadth of possible consequences. Project 3 studies reveal novel, complex roles for the receptor for advanced glycation end products (RAGE; gene name Ager) and its cytoplasmic domain binding partner, DIAPH1, in parenchymal vs. immune cell dysfunctions. Project 3 key discoveries during Cycle 1 of the Program Project include: (1) deletion of Ager or Diaph1 in myeloid cells significantly increases insulin resistance without further increasing body mass in high fat diet-fed mice; (2) RAGE/DIAPH1 contributes to regulation of hepatic lipid metabolism; (3) macrophage RAGE contributes to regulation of Interferon Regulatory Factor 7 (IRF7); IRF7 bridges lipid metabolism and inflammation in macrophages; and (4) in mice fed a non-alcoholic steatohepatitis (NASH)-inducing diet, myeloid deletion of Ager or novel small molecule antagonists of RAGE/DIAPH1 imparts complex consequences on steatosis and fibrosis. These considerations lead us to hypothesize that RAGE/DIAPH1 contributes to regulation of macrophage metabolism; molecular re-programming in response to tissue- and cue-specific stimuli; and macrophage intra- and interorgan communications in cardiometabolic dysfunction. We will pursue three specific aims: Aim 1 will test the hypothesis that DIAPH1 contributes to atherosclerosis through intra- and interorgan regulation of lipid metabolism and inflammation; AIM 2 test the hypothesis that RAGE/DIAPH1/IRF7 uncouples liver steatosis and fibrosis in NASH through regulation of lipid metabolism and dynamic reprogramming of infiltrating Mɸs and resident Kupffer cells; and AIM 3 will test the hypothesis that RAGE/DIAPH1 contributes to cardiometabolic disease through interorgan communications. Project 3, with Projects 1-2, will identify the depot-, cue- and temporal-mediating mechanisms of cardiometabolic dysfunction, driven by macrophages and, critically, their interactions with parenchymal and non-parenchymal niche-specific cells. Fortified by complementary examinations in human tissues and transcriptome databases, we will employ state-of-the-art RNA sequencing, coupled with strategically-utilized spatial transcriptomics, to generate and “visualize” a comprehensive map of the putative interactome and the upstream transcriptional regulators that regulate intra- and interorgan cross- talk in cardiometabolic disorders. This work and the Program Project hold great promise to identify targeted and prudent therapies in atherosclerosis, obesity and NASH through the lens of dysregulated macrophage-evoked communications in metabolic organ networks.

摘要：项目3 我们的计划项目已经揭示了巨噬细胞代谢，仓库，提示和时间范围的关键角色 分子重新编程和在心脏代谢功能障碍的发病机理中进行的 代谢环境，包括动脉粥样硬化斑块，肥胖的脂肪组织和肝脏， 组织特异性的小众，例如过量的脂质含量，以及浸润骨髓的募集和运输 衍生的免疫细胞，该细胞发出信号以激活居民免疫细胞中的内源性信号通路 （例如，脂肪组织巨噬细胞或肝库普弗细胞）定义了可能的构造。 3研究揭示了晚期糖基化终产物受体的新颖，复杂的作用（RAGE； GENE NAMEME） AGER）及其细胞质结合伴侣Diaph1在同章和免疫细胞功能障碍中。 该计划项目的周期1期间的3个主要发现包括：（1）髓样细胞中的耳朵或diaph1的缺失 高脂肪饮食喂养的小鼠的进一步增加了体重，从而显着增加了渐进率；（2） 愤怒/diaph1有助于肝脂质代谢的调节； 调节干扰素调节因子7（IRF7）； 巨噬细胞; 或愤怒/diaph1的新型小分子拮抗剂会赋予脂肪变性和firosis的压缩后果。 这些考虑因素使我们假设Rage/Diaph1有助于巨噬细胞的调节 代谢；对组织和提示特异性刺激的反应 和心脏代谢功能障碍中的跨组织通信。 检验diaph1通过脂质内和间调节导致动脉粥样硬化的假设 代谢和炎症 通过调节脂质代谢和浸润M的动态重编程和动态重新编程，以及 居民kupffer细胞； 通过跨组织通信的疾病。 巨噬细胞驱动的心脏代谢功能障碍的时间介导机制，并至关重要 通过互补的加固，与同与非裂特异性细胞的相互作用 在人体组织和转录组数据库中进行检查，我们将采用最新的RNA测序， 再加上战略利用的空间转录组学，以生成和“可视化”一张综合图 推定的相互作用组和上游的转录调节器 在心脏多核障碍中进行交谈。 动脉粥样硬化，肥胖症和nash透镜的审慎疗法的失调巨噬细胞诱发的镜头 代谢器官网络中的通信。