OXGR1 in Renal Intercalated Cells, Salt Transport and Diuretic Efficacy
OXGR1在肾闰细胞、盐转运和利尿功效中的作用
基本信息
- 批准号:9913504
- 负责人:
- 金额:$ 82.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-10-05 至 2022-04-30
- 项目状态:已结题
- 来源:
- 关键词:AblationAffectAlkalosisAngiotensin IIAnimalsAntihypertensive AgentsApicalBicarbonatesBiochemicalBiologicalBlood PressureCalcineurinCalciumCardiovascular DiseasesCellsChloridesChronic Kidney FailureDataDiagnosticDiarrheaDiseaseDiureticsDuct (organ) structureEffectivenessElectrolyte BalanceElectrophoretic Mobility Shift AssayEssential HypertensionFailureG Protein-Coupled Receptor SignalingG-Protein-Coupled ReceptorsGeneticGenetic TranscriptionGenomicsHealthHypertensionHypokalemiaIn VitroIntercalated CellInvestigationKidneyKnockout MiceKnowledgeLeadLightLinkLiquid substanceMediatingMedicalMetabolicMolecularMolecular TargetMusPathway interactionsPatientsPharmaceutical PreparationsPhenotypePhosphorylationPhysiologicalPhysiologyPlanetsPotassiumProcessPublic HealthPublishingRecombinantsRenal functionResistanceRoleSodium ChlorideStimulusSystemSystems BiologyTestingTherapeutic EffectThiazide DiureticsTranslatingTransport ProcessUnited StatesUrineVomitingWorkabsorptionalpha ketoglutarateapical membraneblood pressure reductioncost effectivedrug discoveryhypertension treatmentkidney cellmultidisciplinarymutantnovelparacrineprogramspromoterreceptorresponsesalt balancesalt sensitivethiazidetooltraffickingtreatment strategyurinarywasting
项目摘要
Thiazides are one of the most cost-effective and medically beneficial first line
antihypertensive agents. However, they don’t work for everyone, and in some
patients they may lower blood pressure for a while but then wear off. The
mechanisms responsible for thiazide resistance have been mysterious, until
recently. Our recent systems-biology investigations revealed a salt-transport
process is activated by a novel mechanism to limit urinary salt wasting when
NCC, the thiazide target, is inhibited or hypokalemic intravascular volume
depletion occurs. We discovered that a salt reabsorption pathway is created by
the coordinate induction of a multi-gene transport system in non-α intercalated
cells, highlighting the Cl/HCO3- exchanger, pendrin, alpha-ketoglutarate (α-KG)
and the α-KG G-Protein Coupled Receptor, OXGR1. Our recently published and
preliminary data strongly suggest that paracrine delivery of α-KG stimulates
OXGR1 in non-α cells and this activates pendrin, stimulates salt reabsorption,
and potentially lowers the diuretic response. Here, we have assembled a highly
collaborative, multidisciplinary team to rigorously test the central tenants of the -
KG /OXGR1/pendrin hypothesis (Aim 1), explore the underlying molecular
mechanism(s) linking OXGR1 to pendrin activation (Aim 2), elucidate the
physiological stimuli and consequences of the Renal α-KG/OxGR1 Paracrine
system (Aim 3), building on our recent discoveries. We expect these
investigations will have a major impact on understanding how the kidney controls
salt balance in health and disease, in ways that illuminate the central
underpinnings of the variable diuretic response. Ultimately, these studies will
provide new information and diagnostic tools that lead to the better treatment of
hypertension.
噻嗪类药物是最具成本效益和医疗效益的一线药物之一
抗高血压药。然而,它们并不适用于所有人,在某些情况下,
对病人来说,它们可能会降低血压一段时间,但随后就会消失。的
噻嗪类药物耐药性的机制一直是个谜,
最近我们最近的系统生物学研究揭示了盐的运输
这一过程被一种新的机制激活,以限制尿盐浪费,
NCC,噻嗪类靶点,被抑制或低钾血症血管内容量
发生了损耗。我们发现盐重吸收途径是由
非α-intercalated多基因转运系统的协同诱导
细胞,突出显示Cl/HCO 3交换剂、pendrin、α-酮戊二酸(α-KG)
和α-KG G蛋白偶联受体,OXGR 1。我们最近出版的和
初步数据强烈提示旁分泌α-KG刺激
OXGR 1在非α细胞中,这激活了pendrin,刺激盐重吸收,
并可能降低利尿反应。在这里,我们聚集了一个高度
协作,多学科团队,严格测试的核心租户,
KG /OXGR 1/pendrin假说(目的1),探索潜在的分子机制
OXGR 1与pendrin激活的联系机制(目的2),阐明了OXGR 1与pendrin激活的关系。
肾α-KG/OxGR 1旁分泌的生理刺激和后果
系统(目标3),建立在我们最近的发现。我们预计这些
研究将对了解肾脏如何控制
盐平衡在健康和疾病,在照亮中央的方式,
可变利尿反应的基础。最终,这些研究将
提供新的信息和诊断工具,从而更好地治疗
高血压
项目成果
期刊论文数量(0)
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会议论文数量(0)
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Eric J Delpire其他文献
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{{ truncateString('Eric J Delpire', 18)}}的其他基金
OXGR1 in Renal Intercalated Cells, Salt Transport and Diuretic Efficacy
OXGR1在肾闰细胞、盐转运和利尿功效中的作用
- 批准号:
10250314 - 财政年份:2019
- 资助金额:
$ 82.5万 - 项目类别:
OXGR1 in Renal Intercalated Cells, Salt Transport and Diuretic Efficacy
OXGR1在肾闰细胞、盐转运和利尿功效中的作用
- 批准号:
10067053 - 财政年份:2019
- 资助金额:
$ 82.5万 - 项目类别:
Coordinated SLC12A3/SLC12A6/SL26A4 electroneutral transport pathways maintain K+ homeostasis and acid-base balance
协调的 SLC12A3/SLC12A6/SL26A4 电中性转运途径维持 K 稳态和酸碱平衡
- 批准号:
10735503 - 财政年份:2017
- 资助金额:
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Molecular and Functional characterization of the first known human mutation of the SLC12A2 gene
第一个已知人类 SLC12A2 基因突变的分子和功能特征
- 批准号:
9095807 - 财政年份:2016
- 资助金额:
$ 82.5万 - 项目类别:
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