Cellular and Molecular Mechanisms of Renal Anemia

肾性贫血的细胞和分子机制

基本信息

批准号：
10587989
负责人：
Volker Hans Haase
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-10-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10587989
关键词：
Adenine Adult Anemia Blood Blood Vessels Cardiovascular system Cell Differentiation process Cell Survival Cell physiology Cells Cellular Metabolic Process Characteristics Chronic Kidney Failure Clinical Research Collagen Complication Data Decarboxylation Development Dioxygenases Electron Transport Electron Transport Complex III Enzymes Erythrocytes Erythroid Progenitor Cells Erythropoiesis Erythropoietin Fibroblasts Fibrosis Functional disorder General Population Genes Genetic Genetic Models Glycoproteins Grant HIF1A gene Heterodimerization Homeostasis Hormones Hydroxylation Hypoxia Hypoxia Inducible Factor In Vitro Incentives Injury Injury to Kidney Intravenous Iron Kidney Kidney Diseases Kidney Failure Knowledge Laboratories Link Metabolic Mitochondria Modeling Molecular Morbidity - disease rate Myofibroblast Nuclear Translocation Oxygen PDGFRB gene Pathogenesis Patients Pericytes Physiological Play Prevalence Procollagen-Proline Dioxygenase Production Proliferating Proline Protein Isoforms Public Health Recombinant Erythropoietin Recombinants Regulation Renal Interstitial Cell Renal function Replacement Therapy Resolution Role Safety Source Three-Dimensional Imaging Transcriptional Regulation Translations United States Ureteral obstruction Veterans Work alpha ketoglutarate bHLH-PAS factor HLF fibrogenesis innovation insight interstitial interstitial cell kidney fibrosis mitochondrial dysfunction mortality mouse model novel novel therapeutic intervention response sensor therapeutic target transcription factor transcriptomic profiling transcriptomics transdifferentiation

项目摘要

Our studies advance knowledge about the cellular and molecular mechanisms that underlie the pathogenesis of anemia associated with chronic kidney disease (CKD), also called renal anemia. CKD represents a major public health burden worldwide and is associated with high cardiovascular morbidity and mortality. In the United States the prevalence of CKD in the general population has been estimated to range between 10 and 15% and is even higher in veterans. Anemia is a classic manifestation of advanced CKD and results from (erythropoietin) EPO deficiency and dyregulated iron homeostasis. The current treatment of renal anemia consists of EPO replacement therapy with recombinant versions of EPO, typically administered in conjunction with intravenous iron. Although recombinant EPO is effective in treating renal anemia, clinical studies have raised significant concerns regarding its cardiovascular safety profile, providing a strong incentive for the development of new therapeutic approaches. EPO deficiency results from the diminished ability of diseased kidneys to produce adequate amounts of the glycoprotein hormone EPO in response to anemia or hypoxia. EPO is essential for red blood production and is produced in the kidney by perivascular fibroblasts and pericytes. In these kidney interstitial cells, oxygen- dependent prolyl 4-hydroxylase domain (PHD) dioxygenases (PHDs) function as the oxygen-sensors that control EPO synthesis by regulating hypoxia-inducible factor (HIF) 2 activity. The inability to activate HIF2 leads to EPO deficiency as shown by our laboratory. Perivascular fibroblasts and pericytes give also rise to myofibroblasts, which promote kidney fibrosis through the enhanced production of collagen and other matrix molecules. Thus, kidney fibrosis and the development of EPO deficiency are directly linked. Despite their importance in erythropoiesis and pathogenesis of kidney fibrosis, very little is known about the metabolic characteristics of renal interstitial cells. In particular, the role of mitochondria in interstitial cell differentiation and function is unclear and has not been investigated. Under this grant, we hypothesize that mitochondria play a central role in the regulation of renal interstitial cell differentiation, HIF2 oxygen sensing and pathogenesis of EPO deficiency in CKD. The application uses genetic mouse models in conjunction with state-of-the-art high resolution 3D imaging of mitochondria, metabolic flux analysis and single cell transcriptomics to investigate a) the role of mitochondrial depletion in renal interstitial cell differentiation and metabolism, b) the role of mitochondria in the regulation of the HIF2/PHD/EPO axis and hypoxia responses in renal interstitial cells, and c) the role of the mitochondrial electron transport chain in the development of EPO deficiency and renal anemia.

我们的研究提高了有关发病机理构成的细胞和分子机制的知识与慢性肾脏疾病（CKD）相关的贫血，也称为肾贫血。 CKD代表一个主要全球公共卫生负担，与高心血管发病率和死亡率有关。在美国估计CKD的普通患病率估计在10至之间 15％，在退伍军人中甚至更高。贫血是高级CKD的经典体现，是（促红细胞生成素）EPO缺乏症和染色的铁稳态。当前的肾脏贫血治疗包括EPO替代疗法与重组版本的EPO版本，通常与静脉输液结合使用。虽然重组EPO可有效治疗肾脏贫血，临床研究引起了重大关注关于其心血管安全性，为开发新治疗提供了强有力的动力方法。 EPO缺乏症是由于患病肾脏产生足够量的能力的降低而导致糖蛋白激素EPO响应贫血或缺氧。 EPO对于红血的产生至关重要由血管周成纤维细胞和周细胞在肾脏中产生。在这些肾脏间质细胞中，氧气依赖性丙酰4-羟化酶结构域（PHD）二加氧酶（PHDS）作为氧气传感器的功能通过调节缺氧诱导因子（HIF）2活性来控制EPO合成。无法激活HIF2 如我们的实验室所示，导致EPO缺乏症。血管周成纤维细胞和周细胞也会产生肌纤维细胞，通过增强胶原蛋白和其他基质的产生来促进肾脏纤维化分子。因此，肾脏纤维化和EPO缺乏的发展直接连接。尽管它们在促红细胞生成和肾纤维化的发病机理中很重要，但对此知之甚少肾脏间质细胞的代谢特征。特别是线粒体在间质细胞中的作用分化和功能尚不清楚，尚未研究。根据这项赠款，我们假设线粒体在调节肾脏间隙细胞中起着核心作用 CKD中EPO缺乏的分化，HIF2氧气传感和发病机理。应用程序使用遗传小鼠模型与最先进的高分辨率3D线粒体成像结合代谢通量分析和单细胞转录组学研究a）线粒体耗竭在肾脏间质细胞分化和代谢，b）线粒体在调节中的作用 HIF2/PHD/EPO轴和肾脏间质细胞中的低氧反应，c）线粒体的作用电子传输链在EPO缺乏和肾脏贫血的发展中。