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.

项目3