Role of GDF15 in the Regulation of Host Tolerance to Inflammation

GDF15 在调节宿主炎症耐受性中的作用

• 批准号: 10320912
• 负责人: Ruslan Medzhitov
• 金额: $ 41.88万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320912
• 关键词: Acute; Affect; Antibodies; Autoimmunity; B-Cell Activation; Blood Circulation; Bone Marrow; Cardiomyopathies; Cardiotoxicity; Cells; Cellular Stress; Data; Disease; Endocrine; Enhancers; Functional disorder; GDF15 gene; GDNF receptors; Heart; Heart failure; Hormones; Hour; Human; Impairment; Infection; Inflammation; Inflammatory; Inflammatory Response; Influenza; Injury; Intravenous; Lead; Ligands; Light; Lipopolysaccharides; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Modeling; Molecular; Monoclonal Antibodies; Morbidity - disease rate; Mus; Neoplasms; Nerve Growth Factor Receptors; Neuroglia; Neurons; Neurotransmitters; Nonesterified Fatty Acids; Nuclear; Organ; Organ failure; Organism; Oxidative Phosphorylation; Pathway interactions; Plasma; Play; Poly I-C; Production; Recombinants; Regulation; Reporting; Role; Sepsis; Signal Transduction; Source; Starvation; Stimulus; Stress; Structure of area postrema; Testing; Therapeutic; Tissue Preservation; Tissues; Toll-like receptors; Triglyceride Metabolism; Triglycerides; Xenobiotics; acute infection; attenuation; cardioprotection; cecal ligation puncture; cytokine; hemodynamics; hindbrain; hypothalamic-pituitary-adrenal axis; improved; in vivo; intraperitoneal; macrophage; mortality; nerve supply; neuronal circuitry; parabrachial nucleus; pathogen; prevent; receptor; response; septic; virtual

PROJECT SUMMARY Growth and Differentiation Factor 15 (GDF15) is highly induced in virtually all inflammatory conditions in humans, including sepsis, cancer and autoimmunity, but its role in the inflammatory response has been unclear. This proposal seeks to understand the role of Growth and Differentiation Factor 15 (GDF15) in mediating protection in sepsis. Preliminary data for this proposal reveals that GDF15 is induced specifically in models of acute infection/inflammation but not other environmental stress conditions and achieves nanogram levels in circulation. The GDF15 receptor, glial cell-lone derived neurotrophic factor receptor alpha-like (GFRAL), was found only in the hindbrain and not induced by inflammation. Blockade of GDF15 led to enhanced mortality in multiple models of sepsis, including lipopolysaccharide (LPS), cecal-ligation puncture (CLP), Poly(I:C), and influenza. Conversely, late administration of recombinant GDF15 led to protection. GDF15 inhibition did not affect inflammatory magnitude or pathogen control. However, GDF15 blockade led to an impairment in the ability of mice to switch to an oxidative phosphorylation state. There was no difference in ketonemia or plasma free fatty acids but a significant decrease in circulating plasma triglycerides. We also found that blockade of GDF15 led to enhanced cardiotoxicity, without a difference in overall hemodynamic control. Thus, GDF15 is a tissue protective hormone. This proposal seeks to test the idea that GDF15 is an adaptive cytokine produced by macrophages in response to acute inflammation, which mediates cardioprotection by controlling triglyceride metabolism via sympathetic innervation.

项目摘要 生长和分化因子15（GDF15）在几乎所有炎症条件下都高度诱导 人类，包括败血症，癌症和自身免疫性，但其在炎症反应中的作用一直是 不清楚。该建议旨在了解增长和分化因子15（GDF15）在 败血症中介导保护。 该提案的初步数据表明，GDF15是在急性模型中专门诱导的 感染/炎症，但没有其他环境压力状况，并在 循环。 GDF15受体，神经胶质细胞衍生的神经营养因子受体α样（GFRAL）是 仅在后脑脑中发现，而不是由炎症引起的。 GDF15的封锁导致死亡率提高 败血症的多种模型，包括脂多糖（LPS），盲肠 - 绑定穿刺（CLP），poly（i：c）和 流感。相反，重组GDF15的晚期给药导致了保护。 GDF15抑制没有 影响炎症大小或病原体控制。但是，GDF15封锁导致 小鼠切换到氧化磷酸化状态的能力。酮症或血浆没有差异 游离脂肪酸，但循环血浆甘油三酸酯的显着降低。我们还发现 GDF15导致了增强的心脏毒性，没有整体血流动力控制差异。因此，GDF15是一个 组织保护激素。该建议旨在测试GDF15是一种自适应细胞因子产生的想法 巨噬细胞响应急性炎症，该炎症通过控制甘油三酸酯介导心脏保护 通过同情神经的代谢。