Role of GDF15 in the Regulation of Host Tolerance to Inflammation

项目摘要 生长和分化因子15（GDF 15）在几乎所有的炎症条件下都是高度诱导的， 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是 不清楚该提案旨在了解生长和分化因子15（GDF 15）在以下方面的作用： 介导脓毒症的保护作用。 该提议的初步数据显示，GDF 15在急性炎症模型中特异性诱导， 感染/炎症，而不是其他环境应激条件，并达到纳克水平， 流通GDF 15受体，胶质细胞孤源性神经营养因子受体α样（GFRAL），是一种神经营养因子受体。 只在后脑发现，而不是由炎症引起的。GDF 15的阻断导致了 多种脓毒症模型，包括脂多糖（LPS）、盲肠结扎穿孔（CLP）、Poly（I：C）和 流感。相反，重组GDF 15的晚期施用导致保护。GDF 15抑制不 影响炎症程度或病原体控制。然而，GDF 15阻断导致了在细胞内的损伤。 小鼠转换到氧化磷酸化状态的能力。在酮血症或血浆中没有差异 游离脂肪酸，但循环血浆甘油三酯显著降低。我们还发现， GDF 15导致心脏毒性增强，但在总体血流动力学控制方面无差异。因此，GDF 15是一种 组织保护激素该提议试图测试GDF 15是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，通过控制甘油三酯介导心脏保护作用 通过交感神经支配进行代谢。

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.