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）的特点是 患病肾脏无法通过产生足够的促红细胞生成素 (EPO) 来应对缺氧， 糖蛋白激素，对于红细胞的生成至关重要，并且还与 绝对性和功能性缺铁。这会导致贫血的发生，这是贫血的临床标志。 晚期 CKD，通常采用重组人 EPO 和静脉铁制剂治疗。 重组 EPO 的使用不仅是晚期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相关，促使 FDA 发布 几个黑框警告。虽然重组人 EPO 的使用已超过 25 年，但 肾性贫血的发病机制尚不清楚。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 氧依赖性调节的关键途径是脯氨酰 4 羟化酶 (PHD) / 缺氧诱导因子（HIF）途径。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 与肾纤维形成密切相关，因为血管周围间质细胞和周细胞不仅是细胞 肾脏中 EPO 的来源，但也产生产生胶原蛋白的肌成纤维细胞。要了解 在细胞和分子水平上调节 CKD 中肾脏 EPO 产生独特的遗传和 药理学工具用于剖析正常和受损肾脏中的 PHD/HIF/EPO 轴。 根据这项资助，我们假设 PHD/HIF 氧传感系统与铁结合 反应元件结合蛋白（IRP）在调节EPO-的分化状态中起着关键作用 产生血管周围间质细胞和周细胞。我们认为异常的 HIF-2 调节会产生 调节细胞分化和功能的特定信号，因此在发病机制中起着至关重要的作用 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 肾损伤条件下的发育，b）表征与相关的分子表型 EPO 生成细胞利用单细胞 RNA 测序技术和 c) 来研究 IRP1 在基线下肾间质细胞 HIF-2 活性和 EPO 产生调节中的作用 和肾损伤情况。