Novel Mechanisms of Decreased NO Bioavailability in Sickle Cell Nephropathy
镰状细胞肾病中 NO 生物利用度降低的新机制
基本信息
- 批准号:8983325
- 负责人:
- 金额:$ 3.33万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-08-01 至 2019-07-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAffectAnimalsBiological AvailabilityBlood VesselsBone Marrow TransplantationChildhoodChronicComplicationDataDeacetylationDevelopmentDiseaseEnd stage renal failureEndothelial CellsEndothelin-1Functional disorderGene ExpressionGenotypeGoalsHematological DiseaseHistonesHypoxiaIndividualInheritedInjuryInterventionKidneyKidney Concentrating AbilityKidney DiseasesKidney FailureKnock-outKnockout MiceLeadLifeLysineMS-275MeasurementMeasuresMediatingMorbidity - disease rateMusNOS3 geneNitric OxideNon-Histone Chromosomal ProteinsOrganPathologyPathway interactionsPatientsPhysiciansPlayProductionProtein IsoformsProteinuriaReactive Oxygen SpeciesRegulator GenesRenal functionRoleScientistSickle CellSickle Cell AnemiaSourceTestingTissuesTrainingTransgenic MiceUnited StatesVascular Endothelial CellVascular EndotheliumVasoconstrictor AgentsVorinostatbasebeta Globinhuman HDAC1 proteinhuman NOS3 proteinimprovedinhibitor/antagonistkidney vascular structuremortalitymouse modelmutantnoveloutcome forecastoverexpressionpreventpublic health relevancereceptorrenal arteryresearch study
项目摘要
DESCRIPTION (provided by applicant): Sickle Cell Disease is the most common inherited blood disorder in the United States and arises when affected individuals are homozygous for a mutant form of beta globin. Renal disease in patients with sickle cell disease (sickle cell nephropathy) occurs in a significant subset of patients and often rapidly progresses to renal failure. Decreased renal vascular nitric oxide production plays a major role in the development of sickle cell nephropathy. However, the mechanisms that contribute to this decreased nitric oxide production are poorly understood. The central hypothesis of the proposed studies is that, within renal vascular endothelial cells, sickle cell disease causes increased endothelin-1 (ET-1) production and increased histone deacetylase 1 (HDAC1) activity that lead to decreased nitric oxide production and, subsequently, renal injury and sickle cell nephropathy. In order to study the contribution of ET-1, we are developing an endothelial-specific ET-1 knockout mouse on a humanized sickle cell disease mouse background. These animals will be studied in order to determine markers of renal vascular nitric oxide production, and additionally, will undergo studies to evaluate renal function and renal injury. To determine the contribution of increased HDAC1 activity in renal vascular endothelial cells, humanized sickle cell disease mice will be treated with the HDAC1 inhibitor MS-275 and the clinically approved HDAC inhibitor, vorinostat. Following treatment, experiments used in the ET-1 aim will be utilized to investigate nitric oxide production, renal function, and renal damage.
描述(由申请人提供):镰状细胞病是美国最常见的遗传性血液疾病,当受影响的个体是β珠蛋白突变形式的纯合子时就会出现。镰状细胞病(镰状细胞肾病)患者的肾脏疾病发生在一个重要的患者亚组中,通常迅速进展为肾衰竭。肾血管一氧化氮生成减少在镰状细胞性肾病的发展中起主要作用。然而,导致这种一氧化氮产生减少的机制知之甚少。拟议研究的中心假设是,在肾血管内皮细胞内,镰状细胞病导致内皮素-1(ET-1)产生增加和组蛋白脱乙酰酶1(HDAC 1)活性增加,导致一氧化氮产生减少,随后导致肾损伤和镰状细胞肾病。为了研究ET-1的贡献,我们正在人源化镰状细胞病小鼠背景上开发内皮特异性ET-1敲除小鼠。将对这些动物进行研究,以确定肾血管一氧化氮产生的标志物,此外,还将进行研究以评价肾功能和肾损伤。为了确定肾血管内皮细胞中增加的HDAC 1活性的贡献,将用HDAC 1抑制剂MS-275和临床批准的HDAC抑制剂伏立诺他处理人源化镰状细胞病小鼠。治疗后,将利用ET-1目标中使用的实验来研究一氧化氮的产生、肾功能和肾损伤。
项目成果
期刊论文数量(0)
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Brandon M Fox其他文献
Brandon M Fox的其他文献
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{{ truncateString('Brandon M Fox', 18)}}的其他基金
Novel Mechanisms of Decreased NO Bioavailability in Sickle Cell Nephropathy
镰状细胞肾病中 NO 生物利用度降低的新机制
- 批准号:
9324987 - 财政年份:2015
- 资助金额:
$ 3.33万 - 项目类别:
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