Renal Mechanisms in Blood Pressure Control
血压控制中的肾脏机制
基本信息
- 批准号:8726472
- 负责人:
- 金额:$ 187.25万
- 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:2013-09-01 至 2018-06-30
- 项目状态:已结题
- 来源:
- 关键词:AccountingAfrican AmericanAnimalsAutomobile DrivingBackBiochemistryBlood PressureBlood flowCell membraneComputersCoupledDahl Hypertensive RatsDevelopmentDiffuseDiffusionDiseaseEventExhibitsFeedsFumarate HydrataseFumaric acidGeneric DrugsGenesGenetic ModelsHomeostasisHumanHydrogen PeroxideHypertensionInfiltrationInjuryIntakeKidneyKidney DiseasesLeadLimb structureMaintenanceMalignant - descriptorMalignant HypertensionMetabolismMicroscopyMitochondriaModelingMolecularMonitorNADPH OxidaseNitric OxideOrganPathway interactionsPerfusionPhasePhysiologicalPlayProcessProductionRattusRectumRenal HypertensionResearchResistanceRoleSignal TransductionSodiumSodium ChlorideStagingSuperoxidesSystemT-LymphocyteTechniquesTestingThickTissuesTransgenic OrganismsTubular formationblood pressure regulationcellular imagingcytokinedesigndisease phenotypefeedingfluorescence imagingfluorophoregenome wide association studyinterstitialneutrophil cytosol factor 67Knovelnovel strategiesnull mutationoverexpressionpressureprogramsprotein expressionresponsesalt intakesalt sensitivesalt sensitive hypertensiontoolvasoconstriction
项目摘要
The integrating theme and unifying hypothesis of this PPG centers on the concept that H202 production in the renal outer medulla (CM) plays a dominant role in the development of salt-sensitive hypertension.
Studies in this PPG will use Dahl salt-sensitive (SS) rats to examine physiological mechanisms and molecular pathways underlying salt-sensitive hypertension; it does not focus on the generic aspects of this disease. This rat model recapitulates many aspects of human salt-sensitive hypertension and demonstrates disease phenotypes which are very similar to those observed in African Americans. Project 1 explores the role of the medullary thick ascending limb (mTAL) and tests the hypothesis that increased salt intake leads to greater mTAL NaCI delivery resulting in excess production of H202 in SS rats as amplified by a greater expression of the p67phox subunit of NADPH oxidase. It is proposed that this results in greater H202 diffusion into the interstitial space thereby constricting vasa recta and reducing medullary perfusion. Project 2 hypothesizes that the initials rise of arterial pressure following an increase in salt intake leads to the infiltration of T-cells in the kidney which exaggerates salt-sensitive hypertension and renal disease by increasing H202 and cytokines. The resulting T-lymphocyte infiltration into the kidney, we propose, is importanfiy influenced by Sh2b3, a gene recently identified by GWAS to be associated with human hypertension. Project 3 hypothesizes that a newly discovered pathway of H202 production related to cellular metabolism contributes importantly to the development and maintenance of hypertension in SS rats. Specifically, fumarase insufficiency in SS rats results in an increase of fumaric acid and glycolytic activity which stimulates H202 production and contributes to the salt-induced hypertension. These conceptually unique hypotheses combined with novel technological tools will advance our understanding of the molecular and physiological mechanisms underlying salt-sensitive hypertension that remain largely unclear. This highly integrated and collaborative program of three projects is supported by an Administrative Core A, the Biochemistry/Microscopy Core B, and Genetic Model Tracking and Monitoring Core C.
这一PPG的整合主题和统一假说集中在这样一个概念上,即肾脏外髓(CM)产生的H202在盐敏感型高血压的发展中起主导作用。
这项PPG研究将使用Dahl盐敏感型(SS)大鼠来检查盐敏感型高血压的生理机制和分子途径;它不关注这种疾病的一般方面。这个大鼠模型概括了人类盐敏感型高血压的许多方面,并展示了与在非裔美国人中观察到的非常相似的疾病表型。项目1探索了延髓粗升肢(MTAL)的作用,并测试了一种假设,即增加盐摄入量会导致更多的mTAL NaCI输送,从而导致SS大鼠H202的过量产生,这是通过NADPH氧化酶的p67Phox亚单位的更大表达而放大的。据认为,这会导致更大的H202扩散到间质间隙,从而收缩直肠血管,减少髓质灌注量。项目2假设,随着盐摄入量的增加,初始动脉压升高会导致T细胞在肾脏中的渗透,这会通过增加H202和细胞因子来夸大盐敏感型高血压和肾脏疾病。我们认为,Sh2b3基因对T淋巴细胞向肾脏的渗入有重要影响,Sh2b3基因最近被GWAS发现与人类高血压有关。项目3假设,一个新发现的与细胞代谢有关的H202产生途径在SS大鼠高血压的发生和维持中起重要作用。特别是SS大鼠富马酸酶缺乏导致富马酸和糖酵解活性增加,从而刺激H202的产生,从而导致盐源性高血压。这些概念上独特的假设与新的技术工具相结合,将促进我们对盐敏感型高血压潜在的分子和生理机制的理解,这些机制在很大程度上仍不清楚。这个由三个项目组成的高度整合和协作的项目得到了管理核心A、生物化学/显微镜核心B和遗传模型跟踪和监测核心C的支持。
项目成果
期刊论文数量(0)
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专利数量(0)
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Allen W Cowley其他文献
Allen W Cowley的其他文献
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{{ truncateString('Allen W Cowley', 18)}}的其他基金
Experimental and computational analysis of mechanisms of mitochondrial-cellular ROS crosstalk in the kidney in salt-sensitive hypertension
盐敏感性高血压肾脏线粒体-细胞 ROS 串扰机制的实验和计算分析
- 批准号:
10529290 - 财政年份:2021
- 资助金额:
$ 187.25万 - 项目类别:
Experimental and computational analysis of mechanisms of mitochondrial-cellular ROS crosstalk in the kidney in salt-sensitive hypertension
盐敏感性高血压肾脏线粒体-细胞 ROS 串扰机制的实验和计算分析
- 批准号:
10321663 - 财政年份:2021
- 资助金额:
$ 187.25万 - 项目类别:
How Can Precision Medicine be Applied to Temporomandibular Disorders and its Comorbidities?
精准医学如何应用于颞下颌关节疾病及其合并症?
- 批准号:
9193954 - 财政年份:2016
- 资助金额:
$ 187.25万 - 项目类别:
Role of NOX4 In Kidney Function In Salt-Sensitive Hypertension
NOX4 在盐敏感性高血压肾功能中的作用
- 批准号:
8886255 - 财政年份:2015
- 资助金额:
$ 187.25万 - 项目类别:
Role of NOX4 In Kidney Function In Salt-Sensitive Hypertension
NOX4 在盐敏感性高血压肾功能中的作用
- 批准号:
9444474 - 财政年份:2015
- 资助金额:
$ 187.25万 - 项目类别:
Genetics and Epigenetics - Temporomandibular Disorders and Related Overlapping Co
遗传学和表观遗传学 - 颞下颌疾病和相关重叠疾病
- 批准号:
8785556 - 财政年份:2014
- 资助金额:
$ 187.25万 - 项目类别:
Comorbid Chronic Pain Conditions - Mechanisms, Diagnosis and Treatments
慢性疼痛共病 - 机制、诊断和治疗
- 批准号:
8203961 - 财政年份:2011
- 资助金额:
$ 187.25万 - 项目类别:
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