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:
- 金额:--
- 依托单位:
- 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:
- 关键词:AdenineAdultAnemiaBloodBlood VesselsCardiovascular systemCell Differentiation processCell SurvivalCell physiologyCellsCellular Metabolic ProcessCharacteristicsChronic Kidney FailureClinical ResearchCollagenComplicationDataDecarboxylationDevelopmentDioxygenasesElectron TransportElectron Transport Complex IIIEnzymesErythrocytesErythroid Progenitor CellsErythropoiesisErythropoietinFibroblastsFibrosisFunctional disorderGeneral PopulationGenesGeneticGenetic ModelsGlycoproteinsGrantHIF1A geneHeterodimerizationHomeostasisHormonesHydroxylationHypoxiaHypoxia Inducible FactorIn VitroIncentivesInjuryInjury to KidneyIntravenousIronKidneyKidney DiseasesKidney FailureKnowledgeLaboratoriesLinkMetabolicMitochondriaModelingMolecularMorbidity - disease rateMyofibroblastNuclear TranslocationOxygenPDGFRB genePathogenesisPatientsPericytesPhysiologicalPlayPrevalenceProcollagen-Proline DioxygenaseProductionProliferatingProlineProtein IsoformsPublic HealthRecombinant ErythropoietinRecombinantsRegulationRenal Interstitial CellRenal functionReplacement TherapyResolutionRoleSafetySourceThree-Dimensional ImagingTranscriptional RegulationTranslationsUnited StatesUreteral obstructionVeteransWorkalpha ketoglutaratebHLH-PAS factor HLFfibrogenesisinnovationinsightinterstitialinterstitial cellkidney fibrosismitochondrial dysfunctionmortalitymouse modelnovelnovel therapeutic interventionresponsesensortherapeutic targettranscription factortranscriptomic profilingtranscriptomicstransdifferentiation
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.
我们的研究增进了对发病机制背后的细胞和分子机制的了解
与慢性肾脏病(CKD)相关的贫血,也称为肾性贫血。 CKD代表主要
全世界的公共卫生负担,并与高心血管发病率和死亡率相关。在
据估计,美国一般人群中 CKD 的患病率在 10 至 10 之间。
15%,退伍军人的比例更高。
贫血是晚期 CKD 的典型表现,是由于(促红细胞生成素)EPO 缺乏和
铁稳态失调。目前肾性贫血的治疗方法包括EPO替代疗法
重组版 EPO,通常与静脉补铁联合使用。虽然
重组EPO治疗肾性贫血有效,临床研究引起关注
关于其心血管安全性,为新疗法的开发提供了强有力的动力
接近。
EPO 缺乏是由于患病肾脏产生足够量 EPO 的能力下降所致。
糖蛋白激素 EPO 对贫血或缺氧的反应。 EPO 对于红血生成至关重要
由肾脏中血管周围成纤维细胞和周细胞产生。在这些肾间质细胞中,氧
依赖脯氨酰 4-羟化酶结构域 (PHD) 双加氧酶 (PHD) 充当氧传感器
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
我们的实验室表明,会导致 EPO 缺乏。血管周围成纤维细胞和周细胞也产生
肌成纤维细胞,通过增强胶原蛋白和其他基质的产生来促进肾纤维化
分子。因此,肾纤维化和 EPO 缺乏的发生直接相关。
尽管它们在红细胞生成和肾纤维化的发病机制中很重要,但人们对它们知之甚少。
肾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,尚未进行研究。
在这笔资助下,我们假设线粒体在肾间质细胞的调节中发挥核心作用
CKD 中 EPO 缺乏的分化、HIF2 氧感应和发病机制。该应用程序使用
遗传小鼠模型与最先进的线粒体高分辨率 3D 成像相结合,
代谢流分析和单细胞转录组学研究 a) 线粒体消耗在
肾间质细胞分化和代谢,b)线粒体在肾间质细胞分化和代谢调节中的作用
HIF2/PHD/EPO 轴和肾间质细胞的缺氧反应,以及 c) 线粒体的作用
EPO 缺乏和肾性贫血发展中的电子传递链。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Poly[[hexa-kis-(μ-benzene-1,4-dicarboxyl-ato)octa-kis-(N,N-dimethyl-acetamide)-hexa-manganese(II)] monohydrate].
聚[[六-kis-(μ-苯-1,4-二羧基-ato)八-kis-(N,N-二甲基乙酰胺)-六锰(II)]一水合物]。
- DOI:
- 发表时间:2011-07-01
- 期刊:
- 影响因子:0
- 作者:Zhang, Ying;Chu, Chao;Li, Yi
- 通讯作者:Li, Yi
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Volker Hans Haase其他文献
Volker Hans Haase的其他文献
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{{ truncateString('Volker Hans Haase', 18)}}的其他基金
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线粒体电子传递功能障碍:剖析病理机制
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