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:8966671
- 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 2017-09-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAllelesAnemiaApplications GrantsBiologyBloodBoxingCardiovascular systemCell LineageCellsCellular biologyCharacteristicsChronic Kidney FailureComplexConsumptionDevelopmentDialysis procedureDioxygenasesEnd stage renal failureErythrocytesErythropoiesisErythropoietinFutureGene Expression RegulationGene TargetingGenesGeneticGenetically Engineered MouseGlycoproteinsGoalsGrantHealthHomeostasisHormonesHypoxiaHypoxia Inducible FactorHypoxia-Inducible Factor PathwayImaging technologyImpairmentIn VitroInjuryKidneyKidney FailureLaboratoriesLinkMeasurementModelingMolecularMolecular ProfilingMorbidity - disease rateNephrologyOxygenPathogenesisPathway interactionsPatient CarePatientsPhysiologicalPopulationProcollagen-Proline DioxygenaseProductionRecombinant ErythropoietinRegulationRegulator GenesRegulatory ElementRenal Interstitial CellRenal functionReninResolutionRoleSafetySiteStressSupportive careTechniquesTransactivationUreteral obstructionVeteransWorkbHLH-PAS factor HLFcell typecostgenetic manipulationgenome-wideimprovedin vivoinjuredinsightinterstitialinterstitial cellkidney cellliver hypoxiamRNA Expressionmortalitynovelnovel therapeuticsresponsetooltranscription factortranscriptome
项目摘要
DESCRIPTION (provided by applicant):
Our long-term goal is to understand the pathogenesis of renal anemia and to develop new and safe therapies for its treatment. Anemia is a classic manifestation of advanced chronic kidney disease (CKD) and results from the diminished ability of the diseased kidney to produce adequate amounts of erythropoietin (EPO), the glycoprotein hormone that is essential for red blood production. Anemia associated with CKD or end stage renal disease (ESRD) is typically treated with recombinant EPO. The use of recombinant EPO not only represents a major cost factor in the care of patients with advanced CKD and ESRD, but also has raised significant cardiovascular safety concerns, which prompted the FDA to issue several black box warnings. While the administration of recombinant EPO to renal patients has been a hallmark of supportive care in Nephrology for more than 20 years, the molecular mechanisms that underlie the pathogenesis of renal anemia are surprisingly poorly understood. A key pathway in the regulation of renal EPO production is the hypoxia-inducible factor (HIF) pathway. Although the hypoxic induction of EPO serves as a paradigm for hypoxic gene regulation, the regulation of renal EPO synthesis under renal injury conditions is incompletely understood on both, the cellular and the molecular level. Over the last 5 years our laboratory and other groups have demonstrated that HIF-2 regulates the hypoxic induction of EPO in the kidney and liver, and that the HIF pathway can be pharmacologically targeted to treat patients with anemia. To understand the regulation of renal EPO production on a cellular and molecular level we have begun to use genetic and pharmacologic approaches to dissect the HIF/EPO axis in normal and in injured kidneys. Under this grant, we hypothesize that HIF-2 controls renal EPO production by regulating renal interstitial cell plasticity. We use genetically engineered mice to a) define the cell types in the kidney that have EPO-producing ability, b) to determine their contribution in the
regulation of erythropoiesis at baseline and under hypoxic stress conditions, c) to characterize the role of the three major HIF prolyl-hydroxylases in the regulation of renal interstitial hypoxia
responses and d) to examine HIF-2 function under renal injury conditions.
描述(由申请人提供):
我们的长期目标是了解肾脏贫血的发病机理,并为其治疗开发新的安全疗法。贫血是晚期慢性肾脏疾病(CKD)的经典表现,是由于患病肾脏产生足够量的促红细胞生成素(EPO)的能力降低,这是糖蛋白激素,这对于红血产生至关重要。与CKD或末期肾脏疾病(ESRD)相关的贫血通常用重组EPO治疗。重组EPO的使用不仅代表了晚期CKD和ESRD患者的护理中的主要成本因素,而且还引起了严重的心血管安全问题,这促使FDA发出了几次黑匣子警告。虽然将重组EPO施用到肾脏患者已成为肾脏科支持性护理的标志已有20多年了,但令人惊讶地了解肾脏贫血发病机理的分子机制。调节肾EPO产生的关键途径是缺氧诱导因子(HIF)途径。尽管EPO的低氧诱导是低氧基因调节的范例,但在肾脏损伤条件下肾脏EPO合成的调节在肾脏损伤条件下的调节在细胞和分子水平上均未完全理解。在过去的五年中,我们的实验室和其他小组表明,HIF-2调节肾脏和肝脏中EPO的低氧诱导,并且可以将HIF途径用于药理靶向治疗贫血患者。为了了解在细胞和分子水平上对肾EPO产生的调节,我们已经开始使用遗传和药理方法在正常和受伤的肾脏中剖析HIF/EPO轴。根据这项赠款,我们假设HIF-2通过调节肾脏间质细胞可塑性来控制肾脏EPO的产生。我们使用基因工程的小鼠来a)定义具有EPO产生能力的肾脏中的细胞类型,b)确定它们在
在基线和低氧应激条件下调节红细胞生成,c)表征三种主要的HIF羟基丙基羟化酶在肾脏间质缺氧调节中的作用
响应和d)检查肾脏损伤条件下的HIF-2功能。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Volker Hans Haase其他文献
Volker Hans Haase的其他文献
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