Christian Faul Pilot

飞行员奖第二名：福尔，克里斯蒂安·H，博士 标题：FGF23在AKI动物模型的全身炎症和心脏损伤中的作用 AKI与院内死亡风险增加有关，并增加了发生CKD的风险。 ESRD，和死亡后很久，最初的AKI事件已经解决。环流高度中的早期高程 骨细胞衍生的磷酸尿激素，成纤维细胞生长因子23，与 AKI患者的不良结局。血清FGF23水平的快速、早期升高也是 报道了两种毒素诱导的AKI小鼠模型(即叶酸和色素的注射 肾病)。尽管增加产量而不是减少淘汰似乎是 AKI中FGF23水平升高，AKI合成和分泌FGF23的来源和机制尚不清楚 可以理解，但似乎独立于FGF23生产的既定监管机构发生，例如 血磷升高。FGF23通过成纤维细胞生长因子受体(FGFR)和Klotho，a 作为FGF23共同受体的跨膜蛋白，从而增加肾脏磷酸盐排泄 以及降低血清磷酸盐水平。慢性肾脏病患者的FGF23反应性和磷酸盐 由于功能性肾脏肿块的丧失和klotho表达的减少，重吸收受到损害，导致 增加血清磷浓度和骨组织中FGF23的生成。慢性肾脏病的临床研究已经 研究表明，血清FGF23水平升高与阴性结局密切相关，如心脏 肥厚和心血管死亡率。FGF23也与较高水平的 慢性肾脏病患者的炎性标志物。我们的翻译工作表明，循环中的FGF23可以直接 导致与慢性肾脏病相关的组织损伤。通过激活成纤维细胞生长因子受体(FGFR)4和随后 磷脂酶Cγ/钙调神经磷酸酶/活化T细胞核因子γ信号转导途径的研究 心肌细胞，FGF23诱导啮齿动物心肌肥大和纤维化。这种病理效应会发生 与Klotho无关。此外，我们还表明，通过激活FGFR4/PLCγ/钙调神经磷酸酶/NFAT 在肝细胞中，FGF23信号通路增加C反应蛋白(CRP)和白介素6的产生 (IL6)，CKD和FGF23升高的动物模型显示肝脏和肝脏中CRP和IL6水平较高。 血。

Pilot Awardee #2: Faul, Christian H., PhD Title: FGF23 Contributes to Systemic Inflammation and Cardiac Injury in Animal Models of AKI AKI is associated with increased risk of in-hospital mortality, and confers greater risks of developing CKD, ESRD, and death long after the initial AKI episode has resolved. Early elevations in circulating levels of the osteocyte-derived phosphaturic hormone, fibroblast growth factor (FGF) 23, are strongly associated with adverse outcomes in patients with AKI. A rapid, early increase in serum FGF23 levels has been also reported in two mouse models of toxin-induced AKI (i.e. administration of folic acid and pigment nephropathy). Although increased production rather than decreased elimination seems to account for elevated FGF23 levels in AKI, the source and mechanism of FGF23 synthesis and secretion in AKI is not understood, but appears to occur independently of established regulators of FGF23 production, such as elevated serum phosphate. FGF23 targets the kidney via FGF receptors (FGFR) and klotho, a transmembrane protein that acts as an FGF23 co-receptor, thereby increasing renal phosphate excretion and lowering serum phosphate levels. In patients with CKD, FGF23-responsiveness and phosphate reabsorption are impaired due to a loss of functional kidney mass and reduced klotho expression, leading to increased serum phosphate concentrations and FGF23 production in bone. Clinical CKD studies have shown that elevated serum FGF23 levels are strongly associated with negative outcomes, such as cardiac hypertrophy and cardiovascular mortality. FGF23 is also strongly associated with higher levels of inflammatory markers in CKD patients. Our translational work indicates that circulating FGF23 can directly contribute to tissue injury that is associated with CKD. By activating FGF receptor (FGFR) 4 and subsequent phospholipase Cγ (PLCγ/calcineurin/nuclear factor of activated T cells (NFAT) signaling in cardiac myocytes, FGF23 induces cardiac hypertrophy and fibrosis in rodents. This pathologic effect occurs independently of klotho. Furthermore, we have shown that by activating FGFR4/PLCγ/calcineurin/NFAT signaling in hepatocytes, FGF23 increases the production of C-reactive protein (CRP) and interleukin 6 (IL6), and animal models with CKD and elevated FGF23 show higher levels of CRP and IL6 in liver and blood.