Translational Studies Examining Soluble EPO Receptor and EPO Resistance in Dialys

检测透析中可溶性 EPO 受体和 EPO 抗性的转化研究

• 批准号: 8049954
• 负责人: RAVI THADHANI
• 金额: $ 32.6万
• 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 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8049954
• 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; Iron; 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; mortality; receptor; response; translational study

DESCRIPTION (provided by applicant): 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 application 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 application has the potential to lead to changes in the diagnosis and management of patients with erythropoietin resistance. PUBLIC HEALTH RELEVANCE: Erythropoietin Resistance in Chronic Renal Failure is a common problem that remains unexplained. Excessive doses of Erythropoietin are linked with increased morbidity and mortality. We will test the hypothesis that Soluble Erythropoietin Receptor circulating in patients with renal failure may contribute to Erythropoietin Resistance in this population.

描述（由申请人提供）：促红细胞生成素是一种生长因子，彻底改变了终末期肾病（ESRD）患者贫血的管理。一些患者仍然面临的一个重大临床挑战是对促红细胞生成素的相对耐药性，这导致使用不断增加的促红细胞生成素剂量和不良后果的风险增加。慢性炎症是促红细胞生成素抵抗的重要因素，但介导这种表型的分子途径尚不清楚。促红细胞生成素通过存在于红细胞中的促红细胞生成素受体（EpoR）起作用。重要的是，可选择的mRNA剪接产生存在于人类血液中的可溶形式的EpoR （sEpoR）。虽然sEpoR的功能尚不清楚，但sEpoR可能调节促红细胞生成素信号，从而提高了这种可溶性受体的生理作用的可能性。没有研究系统地检查ESRD的sEpoR水平。使用ESRD受试者的存档血清样本，我们产生了初步数据，表明sEpoR在他们的血清中作为27kDa蛋白被检测到，并且血清sEpoR水平升高与红细胞生成素需求增加相关。此外，我们有初步的数据表明，在表达EpoR的细胞系中，sEpoR抑制促红细胞生成素介导的信号换能器和转录激活因子5 （Stat-5）磷酸化。我们还在离体研究中证明，sEpoR水平升高的患者的血清阻断了这种磷酸化。本应用的目的是证实高水平sEpoR的血清可以通过外源性促红细胞生成素的救援和血清中sEpoR免疫吸附后的抑制作用来阻断促红细胞生成素介导的体外细胞内信号传导。我们还将研究sEpoR分泌对ESRD中已知升高的炎症介质的反应的调节。最后，我们将进行两项临床研究，使用来自大型透析队列的存档样本（ArMORR，美国；4D，德国）来检验透析开始时sEpoR水平升高独立预测随后的促红细胞生成素剂量的假设。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组成的合作团队解决ESRD患者面临的最常见和最棘手的问题之一。这一应用有可能改变促红细胞生成素抵抗患者的诊断和管理。