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.

晚期慢性肾病（CKD）和终末期肾病（ESRD）的特征在于： 患病的肾脏不能对缺氧做出反应，产生足够的促红细胞生成素（EPO）， 一种糖蛋白激素，对红细胞的生成至关重要，并且还与 绝对和功能性缺铁这导致贫血的发展，贫血的临床标志是 晚期CKD，其通常用重组人EPO和静脉内铁制剂治疗。 重组EPO的使用不仅是治疗晚期乳腺癌患者的主要成本因素， CKD和ESRD，但也与重大心血管风险相关，促使FDA发布 黑盒警告虽然重组人EPO已经使用超过25年， 肾性贫血的发病机制知之甚少。该研究项目的长期目标是 了解肾性贫血发病机制的细胞和分子机制。 肾EPO的氧依赖性调节中的关键途径是脯氨酰-4-羟化酶（PHD）/脯氨酰-4-羟化酶。 缺氧诱导因子（HIF）通路。在过去的10年里，我们的实验室和其他实验室已经证明， HIF-2调节肾脏和肝脏中EPO的缺氧诱导。肾性贫血的发病机制是 与肾纤维化密切相关，因为血管周围间质细胞和周细胞不仅是肾纤维化的细胞， 肾脏中EPO的来源，而且还产生产生胶原蛋白的肌成纤维细胞。了解 在细胞和分子水平上调节CKD中肾脏EPO的产生是一种独特的遗传和 药理学工具用于解剖正常和受损肾脏中的PHD/HIF/EPO轴。 根据这项研究，我们假设PHD/HIF氧传感系统与铁结合， 反应元件结合蛋白（responsible element binding protein，IRP）在调节EPO的分化状态中起关键作用， 产生血管周围间质细胞和周细胞。我们认为异常的HIF-2调节产生 调节细胞分化和功能的特异性信号，因此在发病机制中具有关键作用 肾性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 B）表征与肾损伤条件相关的分子表型， 利用单细胞RNA测序技术生产EPO的细胞，以及c）在研究EPO的表达时， IRP 1在调节肾间质细胞中HIF-2活性和基线下EPO产生中的作用 和肾损伤状况。