Fibrin(ogen) control of metabolic inflammation and obesity

纤维蛋白（原）控制代谢炎症和肥胖

• 批准号: 10065070
• 负责人: MATTHEW J FLICK
• 金额: $ 37.65万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-20 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10065070
• 关键词: Adhesions; Adipocytes; Adipose tissue; Automobile Driving; Binding; Blood coagulation; CD11c Antigens; Cardiovascular Diseases; Cell Surface Receptors; Cells; Chronic; Clinical; Coagulation Process; Coupled; Deposition; Development; Diet; Disease Resistance; Event; Factor XIII; Fatty Liver; Fibrin; Fibrinogen; Fibrinogen Receptors; Functional disorder; Glucose; Goals; Hemostatic function; Hepatocyte; High Fat Diet; Human; Immobilization; Immune; Immunomodulators; Individual; Inflammation; Inflammatory; Instruction; Insulin Resistance; Integrin Binding; Integrins; Knowledge; Leukocytes; Link; Lipids; Liver; Liver diseases; Macrophage Activation; Macrophage-1 Antigen; Malignant Neoplasms; Mediating; Metabolic; Metabolic Control; Metabolic Diseases; Metabolic dysfunction; Metabolic syndrome; Metabolism; Modeling; Molecular; Morbidity - disease rate; Mus; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity associated disease; Outcome; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Phenotype; Population; Proteins; Publishing; Research; Role; Seminal; Structure; Testing; Therapeutic; Thrombosis; Tissues; United States; base; crosslink; cytokine; insight; interest; lipid biosynthesis; macrophage; mortality; mouse model; novel; novel therapeutics; obesity development; obesity treatment; polymerization; programs; receptor; Adhesions; Adipocytes; Adipose tissue; Automobile Driving; Binding; Blood coagulation; CD11c Antigens; Cardiovascular Diseases; Cell Surface Receptors; Cells; Chronic; Clinical; Coagulation Process; Coupled; Deposition; Development; Diet; Disease Resistance; Event; Factor XIII; Fatty Liver; Fibrin; Fibrinogen; Fibrinogen Receptors; Functional disorder; Glucose; Goals; Hemostatic function; Hepatocyte; High Fat Diet; Human; Immobilization; Immune; Immunomodulators; Individual; Inflammation; Inflammatory; Instruction; Insulin Resistance; Integrin Binding; Integrins; Knowledge; Leukocytes; Link; Lipids; Liver; Liver diseases; Macrophage Activation; Macrophage-1 Antigen; Malignant Neoplasms; Mediating; Metabolic; Metabolic Control; Metabolic Diseases; Metabolic dysfunction; Metabolic syndrome; Metabolism; Modeling; Molecular; Morbidity - disease rate; Mus; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity associated disease; Outcome; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Phenotype; Population; Proteins; Publishing; Research; Role; Seminal; Structure; Testing; Therapeutic; Thrombosis; Tissues; United States; base; crosslink; cytokine; insight; interest; lipid biosynthesis; macrophage; mortality; mouse model; novel; novel therapeutics; obesity development; obesity treatment; polymerization; programs; receptor

PROJECT SUMMARY/ABSTRACT Obesity-driven metabolic dysfunction is a driver of cardiovascular disease, type II diabetes, fatty liver disease, thrombosis, and numerous cancers, and thus underlies substantial morbidity and mortality in the United States. In obese humans with metabolic syndrome, and in mouse models of obesity, pathologic outcomes are driven by a chronic inflammatory state of “metabolic inflammation,” in which immune cells (eg, macrophages) and immune modulators (eg, cytokines) hijack normal metabolic function. Coagulation cascade activation is a conspicuous feature of obesity in humans and is similarly prominent in high fat diet (HFD)-challenged mice. Compelling published and new findings from our research team suggest that fibrin deposits in adipose are an important, yet largely unappreciated driver of metabolic inflammation, and a powerful determinant of adipose and liver pathologies in the obese state. The scientific premise for the proposed research is that fibrin(ogen), factor XIII (fXIII), and β2 integrins have all independently been implicated in the pathogenesis of obesity sequelae in experimental obesity. However, the precise mechanism(s) by which fibrin promotes inflammation, including the molecular form of the molecule and the precise cell-surface receptors mediating inflammatory cell activities, remains largely undefined. The central hypothesis framing these studies is that stabilized extravascular fibrin deposits in adipose exacerbate macrophage-mediated metabolic inflammation by engaging leukocyte integrin receptors αMβ2 and αXβ2. The principal objective of this study is to determine the mechanisms whereby shifts in fibrinogen deposits in adipose and liver trigger local inflammatory cell activation and dysfunctional metabolism in experimental obesity Specifically, we will: (i) determine whether the conversion of fibrinogen to crosslinked fibrin matrices and the engagement of the leukocyte integrin receptor αMβ2 are mechanistically coupled to the development of diet-induced obesity and metabolic dysfunction (AIM1); (ii) determine the contribution of immobilized fibrinogen, fibrin, and crosslinked fibrin to β2 integrin-dependent changes in macrophage phenotype as well as macrophage-mediated adipogenesis and lipid accumulation within cells (AIM2); and (iii) determine the systemic and tissue-based changes in metabolism (specifically glucose handling) mediated by fibrin(ogen). (AIM3). The insights gained will significantly advance the current understanding of obesity development and highlight novel therapeutic opportunities centering on fibrin(ogen) in the treatment of obesity-driven metabolic pathologies.

项目摘要/摘要 肥胖驱动的代谢功能障碍是心血管疾病，II型糖尿病，脂肪肝病的驱动力， 血栓形成和众多癌症，因此在美国具有重大发病率和死亡率。 在具有代谢综合征的肥胖人中，在肥胖的小鼠模型中，病理结局是驱动的 通过“代谢炎症”的慢性炎症状态，其中免疫细胞（例如，巨噬细胞）和 免疫调节剂（例如，细胞因子）劫持正常的代谢功能。凝血级联激活是 肥胖症在人类中的明显特征，在高脂饮食（HFD）挑战小鼠中同样突出。 引人注目的研究团队的新发现表明，脂肪中的纤维蛋白沉积是一种 重要但在很大程度上没有批准的代谢注射驱动力，也是脂肪的有力决定因素 和肥胖状态的肝病。拟议研究的科学前提是纤维蛋白（OGEN）， 因子XIII（FXIII）和β2整联蛋白都独立地与肥胖症​​的发病机理有关 实验性肥胖症中的后遗症。但是，纤维蛋白促进注射的精确机制， 包括分子的分子形式和介导炎症细胞的精确细胞表面受体 活动，仍然很大程度上不确定。这些研究的中心假设是稳定 脂肪中的血管外纤维蛋白沉积物通过参与来加剧巨噬细胞介导的代谢注射 白细胞整合素受体αMβ2和αXβ2。这项研究的主要目的是确定 脂肪和肝触发局部炎症细胞激活中纤维蛋白原沉积的机制 特别是实验性肥胖症中的代谢功能失调，我们将：（i）确定是否确定 将纤维蛋白原转化为交联的纤维蛋白材料和白细胞整合素受体的参与度 αMβ2与饮食诱导的肥胖症和代谢功能障碍的发展相结合（AIM1）； （ii）确定固定纤维蛋白原，纤维蛋白和交联纤维蛋白对β2整合素依赖性依赖性的贡献 巨噬细胞表型的变化以及巨噬细胞介导的脂肪形成和脂质积累 在细胞内（AIM2）； （iii）确定代谢的全身性和基于组织的变化（特别是 葡萄糖处理）由纤维蛋白（OGEN）介导。 （AIM3）。获得的见解将大大提高电流 了解肥胖的发展并突出以纤维蛋白（OGE）为中心的新型治疗机会 肥胖驱动的代谢病理的治疗。