Cellular and Molecular Mechanisms of Renal Anemia

肾性贫血的细胞和分子机制

• 批准号: 10265319
• 负责人: Volker Hans Haase
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-10-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265319
• 关键词: 5' Untranslated Regions; Adenine; Affect; Alleles; Anemia; Binding; Cell Differentiation process; Cell physiology; Cells; Chronic Kidney Failure; Clinical; Collagen; Complication; Development; Dialysis procedure; Elements; End stage renal failure; Enrollment; Enzymes; Equilibrium; Erythrocytes; Erythropoietin; Experimental Models; Factor Va; Fibroblasts; Fibrosis; Fluorescent in Situ Hybridization; Gene Expression; Generations; Genetic; Glycoproteins; Goals; Grant; Healthcare Systems; Homeostasis; Hormones; Hypoxia; Hypoxia Inducible Factor; Hypoxia-Inducible Factor Pathway; IRE-Binding Protein; Immunofluorescence Immunologic; Immunohistochemistry; Impairment; Injectable; Injury; Injury to Kidney; Intravenous; Iron; Kidney; Kidney Diseases; Kidney Failure; Knockout Mice; Laboratories; Lead; Link; Liver; Metabolic; Molecular; Molecular Profiling; Morbidity - disease rate; Mutate; Myofibroblast; Oxygen; PDGFRB gene; Pathogenesis; Pathway interactions; Patient Care; Patients; Pericytes; Pharmacology; Phase; Phenotype; Play; Preparation; Procollagen-Proline Dioxygenase; Production; Proteins; RNA; Recombinant Erythropoietin; Regulation; Renal Interstitial Cell; Research Project Grants; Role; Signal Transduction; Source; System; Tamoxifen; Technology; Tissues; Transcript; Transgenic Organisms; Translational Repression; Translations; Ureteral obstruction; Veterans; Veterans Health Administration; Work; bHLH-PAS factor HLF; cancer cell; cardiovascular risk factor; clinical development; cost; factor A; fibrogenesis; improved; interstitial; interstitial cell; iron deficiency; molecular phenotype; mortality; normoxia; novel; novel therapeutics; recombinant human erythropoietin; response; sensor; single-cell RNA sequencing; therapeutic target; therapy development; tool; transcriptome

Advanced chronic kidney disease (CKD) and end stage renal disease (ESRD) are characterized by the inability of the diseased kidney to respond to hypoxia with adequate production of erythropoietin (EPO), the glycoprotein hormone that is essential for the generation of red blood cells, and is furthermore associated with absolute and functional iron deficiency. This leads to the development of anemia, a clinical hallmark of advanced CKD, which is typically treated with recombinant human EPO and intravenous iron preparations. The use of recombinant EPO not only represents a major cost factor in the care of patients with advanced CKD and ESRD, but also is associated with significant cardiovascular risks prompting the FDA to issue several black box warnings. While recombinant human EPO has been in use for over 25 years, the pathogenesis of renal anemia is poorly understood. The long-term goals of this research project are to understand the cellular and molecular mechanisms that underlie the pathogenesis of renal anemia. A key pathway in the oxygen-dependent regulation of renal EPO is the prolyl-4-hydroxylase (PHD) / hypoxia-inducible factor (HIF) pathway. Over the last 10 years our laboratory and others have demonstrated that HIF-2 regulates the hypoxic induction of EPO in kidney and liver. The pathogenesis of renal anemia is intricately linked to renal fibrogenesis, as perivascular interstitial cells and pericytes are not only the cellular sources of EPO in the kidney but also give rise to collagen-producing myofibroblasts. To understand the regulation of renal EPO production in CKD on a cellular and molecular level unique genetic and pharmacologic tools are used to dissect the PHD/HIF/EPO axis in normal and in injured kidneys. Under this grant we hypothesize that the PHD/HIF oxygen sensing system in conjunction with iron responsive element binding protein (IRP) plays a critical role in regulating the differentiation state of EPO- producing perivascular interstitial cells and pericytes. We propose that abnormal HIF-2 regulation generates specific signals that modulate cell differentiation and function and thus has a crucial role in the pathogenesis of renal anemia. Our studies aim at a) elucidating the role of the perivascular PHD/HIF-2 axis in anemia development under renal injury conditions, b) at characterizing molecular phenotype that associates with EPO-producing cells taking advantage of single cell RNA sequencing technology and c) at investigating the role of IRP1 in the regulation of HIF-2 activity in renal interstitial cells and EPO production under baseline and kidney injury conditions.

晚期慢性肾脏疾病（CKD）和末期肾病（ESRD）的特征是 患病的肾脏无法通过足够产生促红细胞生成素（EPO）来应对缺氧， 糖蛋白激素对于生成红细胞必不可少的，并且还相关 具有绝对和功能性铁缺乏症。这导致了贫血的发展，贫血是 晚期CKD，通常用重组人EPO和静脉固定铁制剂处理。 重组EPO的使用不仅代表了晚期患者护理的主要成本因素 CKD和ESRD，但也与重大心血管风险有关，促使FDA发出 几个黑匣子警告。尽管重组人EPO已经使用了25年以上，但 肾脏贫血的发病机理知之甚少。该研究项目的长期目标是 了解肾脏贫血发病机理的基础的细胞和分子机制。 肾EPO的氧气依赖性调节中的关键途径是丙基-4-羟化酶（PHD） / 低氧诱导因子（HIF）途径。在过去的十年中，我们的实验室和其他人证明了 HIF-2调节肾脏和肝脏中EPO的低氧诱导。肾贫血的发病机理是 与肾纤维发生相关，因为周围间质细胞和周细胞不仅是细胞 肾脏中的EPO来源，但也引起产生胶原蛋白的肌纤维细胞。理解 调节CKD中肾脏EPO在细胞和分子水平的独特遗传和 药理工具用于在正常和受伤的肾脏中剖析PHD/HIF/EPO轴。 在这项赠款下，我们假设PhD/HIF氧气传感系统与铁结合 响应元素结合蛋白（IRP）在调节epo-的分化状态中起关键作用 产生血管周间质细胞和周细胞。我们提出异常HIF-2调节会产生 调节细胞分化和功能的特定信号，因此在发病机理中具有至关重要的作用 肾贫血。我们的研究旨在a）阐明血管周围PHD/HIF-2轴在贫血中的作用 肾脏损伤条件下的发育，b）表征与分子表型相关的分子表型 EPO产生细胞利用单细胞RNA测序技术，c）研究 IRP1在基线下肾脏间隙细胞和EPO产生中HIF-2活性调节中的作用 和肾脏损伤状况。