Soluble EPO Receptor and EPO Resistance in Dialysis

促红细胞生成素是一种生长因子，它彻底改变了贫血的治疗 终末期肾病(ESRD)患者。一项重大的临床挑战 在一些患者中残留的是促红细胞生成素的相对抵抗力，这导致使用 连续增加促红细胞生成素剂量和增加不良结果的风险。 慢性炎症是促红细胞生成素抵抗的重要因素，但 调节这一表型的分子途径尚不清楚。促红细胞生成素作用 通过红细胞中存在的促红细胞生成素受体(EPOR)。重要的是 选择性的mRNA剪接产生一种可溶性形式的EPOR(SEpoR)，它存在于 人血。虽然sEpoR的功能尚不清楚，但sEpoR可能会调节 促红细胞生成素信号，提高了这一可溶性的生理作用的可能性 受体。还没有研究系统地检测ESRD的sEpoR水平。vbl.使用 从ESRD患者身上获得的存档血清样本，我们已经生成了 初步数据显示，在他们的血清中可以检测到27 kDa的sEpoR蛋白，以及 较高的血清sEpoR水平与促红细胞生成素需求增加相关。在……里面 此外，我们有初步数据表明sEpoR抑制促红细胞生成素 介导的信号转导和转录激活因子5(Stat-5)磷酸化 表达EPOR的细胞系。我们还证明，高血压病患者的血清 在体外研究中，sEpoR水平阻止了这种磷酸化。这项提议的目的是 证实sEpoR高水平血清可阻断促红细胞生成素的介导 外源性促红细胞生成素对细胞内信号转导的影响及抑制作用 免疫吸附sEpoR后对血清的影响我们还将研究 已知炎症介质对sEpoR分泌的调节作用 终末期肾病升高。最后，我们将使用存档样本进行两项临床研究。 来自大型透析队列(ARMORR，美国；4D，德国)，以检验以下假设 透析开始时sEpoR水平升高可独立预测后续 促红细胞生成素剂量。我们相信这种探索性的R21机制将允许 由基础科学家和临床研究人员组成的协作团队将解决 终末期肾病患者面临的最常见和最令人烦恼的问题。这项建议具有 可能导致患者诊断和管理的变化 促红细胞生成素抵抗。

Erythropoietin is a growth factor that has revolutionized the management of anemia in patients with end-stage renal disease (ESRD). A significant clinical challenge that remains in some patients is the relative resistance to erythropoietin, which leads to use of successively higher erythropoietin doses and increased risk of adverse outcomes. Chronic inflammation is an important factor contributing to erythropoietin resistance, yet the molecular pathways mediating this phenotype are unclear. Erythropoietin acts through the erythropoietin receptor (EpoR) present in erythroblasts. Importantly, alternative mRNA splicing produces a soluble form of EpoR (sEpoR) that is present in human blood. While the function of sEpoR is unknown, sEpoR may modulate erythropoietin signaling, raising the possibility of a physiologic role for this soluble receptor. No studies have systematically examined sEpoR levels in ESRD. Using archived serum samples obtained from subjects with ESRD, we have generated preliminary data to show that sEpoR is detectable as a 27kDa protein in their serum, and that higher serum sEpoR levels correlate with increased erythropoietin requirements. In addition we have preliminary data suggesting that sEpoR inhibits erythropoietin mediated signal transducer and activator of transcription 5 (Stat-5) phosphorylation in cell lines expressing EpoR. We also demonstrate that serum from patients with elevated sEpoR levels blocks this phosphorylation in ex vivo studies. The intent of this proposal is to confirm that serum with high levels of sEpoR can block erythropoietin mediated intracellular signaling in vitro by rescue with exogenous erythropoietin and inhibition of the effect after immunoadsorption of sEpoR from the serum. We will also examine the regulation of sEpoR secretion in response to inflammatory mediators known to be elevated in ESRD. Finally, we will perform two clinical studies using archived samples from large dialysis cohorts (ArMORR, US; 4D, Germany) to test the hypothesis that elevated sEpoR levels at the start of dialysis independently predict subsequent erythropoietin dose. We believe this exploratory R21 mechanism will permit a collaborative team of basic scientists and clinical investigators to address one of the most common and vexing problems faced by ESRD patients. This proposal has the potential to lead to changes in the diagnosis and management of patients with erythropoietin resistance.