Christian Faul Pilot

克里斯蒂安·福尔飞行员

• 批准号: 9592094
• 负责人: Christian Faul
• 金额: $ 5.96万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9592094
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Animal Model; Area; Blocking Antibodies; Blood; C-reactive protein; Calcineurin; Calcineurin inhibitor; Cardiac; Cardiac Myocytes; Cardiovascular system; Cell Surface Receptors; Cessation of life; Chronic Kidney Failure; Clinical; Co-Immunoprecipitations; Cyclosporine; Disease; Distant; Doctor of Philosophy; Drug Targeting; Echocardiography; End stage renal failure; Enzyme-Linked Immunosorbent Assay; Excretory function; FGFR4 gene; Fibroblast Growth Factor Receptors; Folic Acid; Gene Targeting; Harvest; Heart; Heart Hypertrophy; Heart Injuries; Hepatic; Hepatocyte; Histologic; Hormones; Hospital Mortality; Immunoblotting; Immunofluorescence Microscopy; Impairment; Individual; Inflammation; Inflammatory; Injections; Injury; Integral Membrane Protein; Interleukin-6; Kidney; Kidney Diseases; Liver; Metabolism; Minerals; Molecular; Morphology; Mus; Myocardium; Operative Surgical Procedures; Organ; Osteocytes; Outcome; PPP3CA gene; Pathologic; Patients; Pharmacology Study; Phospholipase C; Pigments; Production; Proteins; Protocols documentation; Renal Mass; Reperfusion Injury; Reporting; Research; Risk; Rodent; Rodent Model; Serological; Serum; Signal Transduction; Source; Testing; Time; Tissues; Toxin; Ventricular Remodeling; Work; adverse outcome; bone; coronary fibrosis; cytokine; fibroblast growth factor 23; fibroblast growth factor receptor 4; functional loss; in vivo Model; inflammatory marker; inorganic phosphate; longitudinal analysis; mortality; mouse model; novel therapeutics; nuclear factors of activated T-cells; phospholipase C gamma; prevent; receptor; renal ischemia

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.

试点获奖者 #2：Faul, Christian H., 博士 标题：FGF23 导致 AKI 动物模型中的全身炎症和心脏损伤 AKI 与院内死亡风险增加相关，并增加罹患 CKD 的风险， 终末期肾病 (ESRD)，以及在最初的 AKI 发作消退很久之后死亡。循环水平的早期升高 骨细胞衍生的磷酸盐激素、成纤维细胞生长因子 (FGF) 23 与 AKI 患者的不良后果。血清 FGF23 水平快速、早期升高也已被证实。 据报道，两种毒素诱导的 AKI 小鼠模型（即给予叶酸和色素 肾病）。尽管产量增加而不是消除减少似乎是原因 AKI时FGF23水平升高，AKI时FGF23合成和分泌的来源和机制尚不明确 理解，但似乎独立于 FGF23 生产的既定调节因子而发生，例如 血清磷酸盐升高。 FGF23 通过 FGF 受体 (FGFR) 和 klotho（一种 作为 FGF23 辅助受体的跨膜蛋白，从而增加肾脏磷酸盐排泄 并降低血清磷酸盐水平。在 CKD 患者中，FGF23 反应性和磷酸盐 由于功能性肾质量损失和 klotho 表达减少，重吸收受损，导致 增加血清磷酸盐浓度和骨骼中 FGF23 的产生。临床 CKD 研究已 研究表明，血清 FGF23 水平升高与负面结果密切相关，例如心脏疾病 肥厚和心血管死亡率。 FGF23 还与较高水平的 CKD 患者的炎症标志物。我们的翻译工作表明循环 FGF23 可以直接 导致与 CKD 相关的组织损伤。通过激活 FGF 受体 (FGFR) 4 及后续 心脏中磷脂酶 Cγ（PLCγ/钙调神经磷酸酶/活化 T 细胞核因子 (NFAT) 信号传导） FGF23 会诱导啮齿动物的心肌细胞肥大和纤维化。这种病理效应的发生 独立于克洛托。此外，我们还表明，通过激活 FGFR4/PLCγ/钙调神经磷酸酶/NFAT FGF23 促进肝细胞中的信号传导，增加 C 反应蛋白 (CRP) 和白细胞介素 6 的产生 (IL6)，患有 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。