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.

项目总结 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，但其在炎症反应中的作用一直 不清楚。本提案旨在了解生长和分化因子15(GDF15)在 败血症的中介保护作用。 这一提议的初步数据显示，GDF15在急性脑梗塞模型中特异性地诱导 感染/炎症，而不是其他环境应激条件，并达到纳克水平 发行量。GDF15受体是胶质细胞源性神经营养因子受体α样受体。 仅在后脑发现，不是由炎症引起的。封锁GDF15导致#年死亡率增加 多种脓毒症模型，包括内毒素(LPS)、盲肠结扎穿刺术(CLP)、Poly(I：C)和 流行性感冒。相反，晚期给予重组GDF15会产生保护作用。GDF15抑制作用不明显 影响炎症程度或病原体控制。然而，GDF15的封锁导致了 小鼠切换到氧化磷酸化状态的能力。在酮血症和血浆中没有差别。 但循环中血浆甘油三酯显著下降。我们还发现，封锁 GDF15导致心脏毒性增强，但对总体血流动力学控制没有影响。因此，GDF15是一个 组织保护性激素。这项提议试图验证GDF15是一种产生的适应性细胞因子的想法 巨噬细胞对急性炎症的反应，通过控制甘油三酯来调节心脏保护 通过交感神经的代谢。