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

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 肥胖导致的代谢功能障碍是心血管疾病、II型糖尿病、脂肪肝、 血栓形成和许多癌症，因此是美国相当大的发病率和死亡率的基础。 在患有代谢综合征的肥胖人类和肥胖的小鼠模型中，病理结果是由 通过“代谢性炎症”的慢性炎症状态，免疫细胞(如巨噬细胞)和 免疫调节剂(如细胞因子)劫持了正常的代谢功能。凝固级联激活是一种 这是人类肥胖的显著特征，在高脂饮食(HFD)挑战的小鼠中也同样显著。 我们研究团队发表的令人信服的新发现表明，脂肪中的纤维蛋白沉积是一种 代谢性炎症的重要，但在很大程度上没有被认识到的驱动因素，以及脂肪的强大决定因素 以及肥胖状态下的肝脏病理。拟议研究的科学前提是纤维蛋白(原)， 凝血因子XIII和β2整合素都独立地参与了肥胖的发病机制 实验性肥胖的后遗症。然而，纤维蛋白促进炎症的确切机制(S)， 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，在很大程度上仍然没有定义。构成这些研究的中心假设是 脂肪中血管外纤维蛋白沉积通过参与巨噬细胞介导的代谢性炎症 白细胞整合素受体αMβ2和αXβ2。本研究的主要目的是确定 脂肪和肝脏中纤维蛋白原沉积变化引发局部炎症细胞激活的机制 和实验性肥胖症的代谢紊乱，我们将：(I)确定是否 纤维蛋白原向交联型纤维蛋白基质的转化及白细胞整合素受体的结合 αMβ2与饮食诱导的肥胖和代谢功能障碍(AIM1)的发展是机械耦合的； (Ii)确定固定化纤维蛋白原、纤维蛋白和交联型纤维蛋白对β2整合素依赖的贡献 巨噬细胞表型变化及巨噬细胞介导的脂肪生成和脂肪堆积 细胞内(AIM2)；以及(Iii)确定系统和基于组织的代谢变化(特别是 葡萄糖处理)由纤维蛋白(原)介导。(AIM3)。所获得的洞察力将显著推动当前 了解肥胖的发展并突出以纤维蛋白(原)为中心的新的治疗机会 肥胖驱动的代谢病理的治疗。