Soluble EPO Receptor and EPO Resistance in Dialysis

透析中可溶性 EPO 受体和 EPO 抵抗

• 批准号: 8204522
• 负责人: RAVI THADHANI
• 金额: $ 17.55万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-06 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8204522
• 关键词: Acute Erythroblastic Leukemia; Address; Amino Acid Sequence; Anemia; Archives; Blood; Blood Transfusion; Cell Line; Characteristics; Chronic; Chronic Kidney Failure; Clinical; Clinical Investigator; Clinical Research; Clinical Trials; Data; Development; Diagnosis; Dialysis patients; Dialysis procedure; Dose; End stage renal failure; Erythroblasts; Erythrocytes; Erythropoiesis; Erythropoietin; Erythropoietin Receptor; Europe; Excision; Exploratory/Developmental Grant; German population; Germany; Growth Factor; Hemodialysis; Hemoglobin concentration result; Human; Immunoprecipitation; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-6; K-562; Kidney Failure; Lead; Left Ventricular Hypertrophy; Link; Mediating; Messenger RNA; Molecular; Morbidity - disease rate; Outcome; Pathway interactions; Patients; Peptide Sequence Determination; Pharmaceutical Preparations; Phenotype; Phosphorylation; Physiological; Play; Population; Production; Proteins; Quality of life; RNA Splicing; Receptor Cell; Recombinant Erythropoietin; Regulation; Relative (related person); Resistance; Risk; Role; STAT protein; Sampling; Scientist; Serum; Signal Transduction; TNF gene; Testing; Transferrin Receptor; Uremia; adverse outcome; cohort; cytokine; design; hepcidin; improved; iron deficiency; mortality; receptor; response

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.

促红细胞生成素是一个增长因素，彻底改变了贫血的管理 末期肾脏疾病（ESRD）的患者。一个重大的临床挑战 在某些患者中仍然存在相对抗红细胞生成素的耐药性，这导致使用 依次更高的红细胞生成剂剂量和增加不良后果的风险。 慢性炎症是导致促红细胞生成素耐药性的重要因素 介导这种表型的分子途径尚不清楚。红细胞生成素的作用 通过红细胞中存在的红细胞生成素受体（EPOR）。重要的是， 替代mRNA剪接会产生一种可溶性的Epor（Sepor），存在于 人血。尽管Sepor的功能尚不清楚，但SEPOR可能会调节 红细胞生成素信号传导，提高了该可溶性生理作用的可能性 受体。没有研究在ESRD中系统地检查了SEPOR水平。使用 从具有ESRD受试者获得的存档血清样品，我们已经生成了 初步数据表明，SEPOR在其血清中可检测为27KDA蛋白，并且 较高的血清SEPOR水平与促红细胞生成素的需求相关。在 此外，我们还有初步数据表明SEPOR抑制红细胞生成素 转录5（Stat-5）磷酸化的介导信号换能器和激活因子 表达Epor的细胞系。我们还证明了来自升高患者的血清 SEPOR水平在离体研究中阻止了这种磷酸化。该提议的目的是 为了确认高水平的Sepor可以阻塞红细胞生成素的介导 通过外源红细胞生成素营救并抑制细胞内信号传导 SEPOR从血清免疫吸收后的作用。我们还将检查 响应于已知的炎症介质的响应Sepor分泌的调节 在ESRD中升高。最后，我们将使用存档样品进行两项临床研究 从大型透析队列（Armorr，美国；德国4D）来检验以下假设。 透析开始时的Sepor水平升高，独立预测随后的 红细胞生成剂剂量。我们相信这种探索性R21机制将允许 基础科学家和临床研究人员的合作团队，以解决其中一项 ESRD患者面临的最常见和烦恼的问题。该提议有 可能导致患者的诊断和管理变化 促红细胞生成素耐药性。