Adiposity Induced Dysfunction of the Endothelin System
肥胖引起的内皮素系统功能障碍
基本信息
- 批准号:8701531
- 负责人:
- 金额:$ 42.53万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:AccountingAddressAfrican AmericanAgonistAngiotensin IIAngiotensin ReceptorAnimal ModelAnimalsAttenuatedBloodBlood CirculationBlood PressureBlood VesselsCardiovascular DiseasesChronicDataDevelopmentDietDiseaseEndothelinEndothelin ReceptorEndothelin-1EquilibriumEssential HypertensionExcretory functionFatty acid glycerol estersFunctional disorderFundingGeneticGoalsGuidelinesHomeostasisHumanHypertensionImpairmentIndividualInflammationInfusion proceduresKidneyKnowledgeLaboratoriesMeasuresMediatingMethodsModelingNatriuresisNerveObesityPhysiciansPhysiologicalPlasmaPlayPrevention strategyProductionPublic HealthRattusRegulationRenal functionRenin-Angiotensin-Aldosterone SystemResearch PersonnelRiskRisk FactorsRoleSodiumSodium ChlorideSodium-Restricted DietSprague-Dawley RatsStressSystemTestingTranslatingTubular formationUnited States Food and Drug AdministrationVasoconstrictor AgentsVasodilationVisitWateracute stresscardiovascular risk factorcell typehuman subjectkidney vascular structurenovel strategiespre-clinicalprogramsreceptorreceptor functionresponsesalt intakesaluretictreatment strategy
项目摘要
The US Food and Drug¿ Administration recently announced new guidelines for recommended levels of salt intake in our diet. These guidelines highlight the fact that certain individuals are at greater risk for the cardiovascular consequences of a high salt intake. The current proposal seeks to define the mechanisms by which risk factors, such as adiposity and environmental stress, contribute to vascular and renal dysfunction associated with the control of sodium balance. The autcicoid, endothelin (ET)-1, functions through ETA and ETB receptors located in a wide range of cell types. Animal studies have revealed an important role for renal tubular ETB receptors in facilitating sodium excretion. Recent studies from the previous funding period have demonstrated that a high fat diet leads to impairment of ETB receptor dependent natriuresis. Therefore, a major goal of the current project is to determine the mechanisms by which adiposity leads to ETB receptor dysfunction to produce alterations in sodium homeostasis, this includes examining a role for angiotensin II and renal sympathetic nerves. In both human and animal models, investigators in the current PPG have observed that acute stress increases plasma ET-1 concentrations. Investigators in Project 1 demonstrated that acute stress in a subpopulation of subjects results in inappropriate Na excretion for a given level of blood pressure. We have also demonstrated that the blood pressure response to acute stress in the Dahl S rat can be attenuated with a combined ETAlB receptor antagonist, but not a selective ETA antagonist. Thus, we propose to explore the degree to which adiposity and genetic factors contribute to ETB receptor function in humans. These issues will be addressed by four aims, two utilizing the Dahl S model that mimics human salt-sensitivity such as frequently occurs in African Americans, and two aims utilizing human subjects. Aim
1 will test the hypothesis that angiotensin II and sympathetic nerve activity mediate ETB receptor dysfunction
in a model of adiposity/pre-hypertension, the Dahl S rat on a high fat diet. Aim 2 will test the hypothesis that
adiposity results in whole body sodium retention and inflammation that caused by reduced ETB and increased ETA receptor function in the Dahl S rat. Aim 3 will test the hypothesis that the magnitude of the blood pressure response to acute stress in humans is increased as a result of reduced ETB receptor activity. Aim 4 will test the hypothesis that obesity is associated with ETB receptor dysfunction in humans due to actions of angiotensin II.
美国食品和药物政府最近宣布了有关饮食中建议水平摄入量的新准则。这些准则强调了这样一个事实,即某些人面临高盐摄入量的心血管后果的风险。当前的提案旨在定义诸如肥胖和环境压力之类的风险因素有助于与钠平衡控制相关的血管和肾功能障碍的机制。 ETCICOID,内皮素(ET)-1,通过位于多种细胞类型的ETA和ETB受体的功能。动物研究揭示了肾小管ETB受体在支撑钠极端方面的重要作用。上一个资金时期的最新研究表明,高脂肪饮食会导致ETB受体依赖性纳地尿症受损。因此,当前项目的一个主要目标是确定肥胖导致ETB受体功能障碍产生钠稳态改变的机制,其中包括检查血管紧张素II和肾交感神经的作用。在人类和动物模型中,当前PPG中的研究人员都观察到急性应激会增加血浆ET-1浓度。项目1中的研究人员表明,受试者亚群中的急性应激导致给定的血压水平不适当地排泄。我们还证明,DAHL S大鼠急性应激的血压反应可以通过组合的ETALB受体拮抗剂减弱,但不能选择性ETA拮抗剂。这是我们建议探索肥胖和遗传因素有助于人类ETB受体功能的程度。这些问题将由四个目标解决,两个目标利用达尔的模型模仿了人类盐敏感性,例如在非裔美国人中经常发生,而两个目标则使用人类受试者。目的
1将测试血管紧张素II和交感神经活动介导ETB受体功能障碍的假设
在肥胖/催眠前的模型中,达尔的大鼠高脂肪饮食。 AIM 2将检验以下假设
AIM 4将检验以下假设:由于ETB受体活性降低,血压对人体急性应激的大小会增加。 AIM 4将检验以下假设:由于血管紧张素II的作用,肥胖与人类的ETB受体功能障碍有关。
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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DAVID M POLLOCK其他文献
DAVID M POLLOCK的其他文献
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Deep South KUH Premier Research - Interdisciplinary Mentored Education (PRIME) Training Core
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Timing of Diet and Kidney Pathophysiology in Diet-Induced Obesity
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10735631 - 财政年份:2023
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$ 42.53万 - 项目类别:
Integrating novel mechanisms controlling sodium excretion and blood pressure
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9922350 - 财政年份:2017
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Integrating novel mechanisms controlling sodium excretion and blood pressure
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ENDOTHELIN CONTROL OF RENAL HEMODYNAMIC AND EXCRETORY FUNCTION
内皮素对肾脏血流动力学和排泄功能的控制
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8464198 - 财政年份:2010
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$ 42.53万 - 项目类别:
ENDOTHELIN CONTROL OF RENAL HEMODYNAMIC AND EXCRETORY FUNCTION
内皮素对肾脏血流动力学和排泄功能的控制
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8125044 - 财政年份:2010
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$ 42.53万 - 项目类别:
ENDOTHELIN CONTROL OF RENAL HEMODYNAMIC AND EXCRETORY FUNCTION
内皮素对肾脏血流动力学和排泄功能的控制
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8661220 - 财政年份:2010
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$ 42.53万 - 项目类别:
ENDOTHELIN CONTROL OF RENAL HEMODYNAMIC AND EXCRETORY FUNCTION
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