N-methyl-D-aspartate receptors (NMDAr) participates in renal hemodynamic regulation and blood pressure homeostasis
N-甲基-D-天冬氨酸受体(NMDAr)参与肾脏血流动力学调节和血压稳态
基本信息
- 批准号:10555201
- 负责人:
- 金额:$ 10.45万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-01-07 至 2025-12-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdvisory CommitteesAgonistAmino AcidsAnimalsApicalAreaArteriesBiologicalBlood PressureCalciumCalcium ChannelCalpainCardiovascular DiseasesCellsCommunicationCritical ThinkingDataDevelopmentDevelopment PlansDialysis procedureDietDiseaseDuct (organ) structureEducational process of instructingElectrophysiology (science)EpitheliumExcretory functionFeedbackFunctional disorderFundingGeneticGenetic TranscriptionGlomerular Filtration RateGlutamatesGlycineGoalsHeart DiseasesHematological DiseaseHumanHypertensionImaging TechniquesImpairmentIn VitroIndividualInternationalKidneyKnockout MiceLabelLaboratoriesLiddle syndromeMediatingMentorsMolecularMusMyocardial InfarctionN-Methyl-D-Aspartate ReceptorsN-MethylaspartateNational Heart, Lung, and Blood InstitutePathway interactionsPatientsPeptide HydrolasesPerfusionPhysiologicalPreventionPrincipal InvestigatorProteomicsPublicationsRegulationResearchResistanceRisk FactorsRoleSignal TransductionSodiumSodium ChlorideSpectrum AnalysisStrokeTechniquesTestingTubular formationUniversitiesUrineVasodilationantagonistarteriolebenzamilblood pressure elevationblood pressure regulationcardiovascular risk factorcareercareer developmentconfocal imagingepithelial Na+ channelexperiencefallshemodynamicshypertensivein vivoinhibitormRNA Expressionmortalitynormotensivenovel therapeuticsprogramsprotein protein interactionskillstherapeutic development
项目摘要
Abstract
Internationally, hypertension is the leading single risk factor for mortality. However, in more than 90% of
hypertensive patients, the cause is unknown. There is a critical need to understand the mechanisms behind
the origins of hypertension to enable the development of new therapies. Connecting tubule-glomerular
feedback (CNTGF) is an epithelial sodium channel (ENaC)-dependent kidney feedback mechanism that
facilitates sodium excretion under certain physiological situations by inducing vasodilation. It has been
previously demonstrated that amino acids, mediated by the N-methyl-D-aspartate receptors (NMDAr), can
induce renal vasodilation. The NMDAr-induced vasodilation mechanism is unknown. Dr. Romero’s long-term
objectives are to explore the consequences of impaired vasodilation in the kidney as a cause of hypertension
and develop a program to thoroughly understand some of the causes of human hypertension. The main
hypothesis is that the mechanisms of NMDAr-mediated vasodilation and CNTGF are closely related and that
impairments of these biological pathways induce hypertension. The hypothesis will be addressed through the
following specific aims. AIM I: To determine the mechanism of NMDAr-induced renal vasodilation. We will
evaluate the role of NMDAr in CNTGF-induced vasodilation in vitro using microperfusion, and in-vivo using
NMDAr NR2C null mice. Aim II: To determine the mechanism by which NMDAr interacts with ENaC.
Using tubule microperfusion, electrophysiology, confocal imaging techniques, and proteoteomic approaches,
we will explore the molecular signaling associated with the interaction between NMDAr and ENaC which
induces the vasodilation. Aim III: To test the effect of NMDAr on blood pressure and renal
hemodynamics. We will evaluate the role of NMDA on blood pressure and renal hemodynamics by treating
ENaC channel gain-in-function mice (Liddle syndrome) with NMDAr inhibitors. The objective and hypothesis of
this proposal align with those of the NHLBI that promote the prevention and treatment of heart and blood
diseases by stimulating basic discoveries about the causes of diseases. Dr. Romero’s development plan
during these funding years include: 1) Increasing his research experience by consolidating the microperfusion
technique and exploring two new areas relating to electrophysiology and proteomics while expanding his
critical thinking and laboratory management skills; 2) Increasing his teaching and mentoring experience; 3)
Further developing his communication skills and publication record. Dr. Romero will be guided by Dr. Wall as a
principal mentor as well as Dr. Eaton and Dr. Hoover as a co-mentors. In addition, an advisory committee will
be supporting the development of this plan. Dr. Romero’s career goal is to be an independently funded
principal investigator in a highly ranked U.S. university to study renal hemodynamics and tubular transport
interactions and their roles in hypertension. This career development plan will be performed entirely at Emory
University, GA, USA.
摘要
在国际上,高血压是导致死亡的主要单一危险因素。然而,在90%以上的
高血压患者,病因不明。我们迫切需要了解
高血压的起源,使新的治疗方法的发展。连接管-肾小球
反馈(CNTF)是上皮钠通道(ENaC)依赖性肾反馈机制,
在某些生理情况下通过诱导血管舒张促进钠排泄。已经
先前证明,由N-甲基-D-天冬氨酸受体(NMDAr)介导的氨基酸可以
诱导肾血管舒张。NMDAr诱导的血管舒张机制尚不清楚。罗梅罗博士的长期
目的是探讨肾脏血管舒张功能受损作为高血压病因的后果
并开发一个程序来彻底了解人类高血压的一些原因。主要
有一种假说认为NMDAr介导的血管舒张机制与CNTF密切相关,
这些生物学途径的损伤诱发高血压。该假设将通过
具体目标。目的一:探讨NMDA受体引起肾血管舒张的机制。我们将
使用微灌注在体外评估NMDAr在CNTGF诱导的血管舒张中的作用,使用微灌注在体内评估NMDAr在CNTGF诱导的血管舒张中的作用。
NMDAr NR 2C缺失小鼠。目的二:确定NMDAR与ENaC相互作用的机制。
使用小管微灌注、电生理学、共聚焦成像技术和蛋白质组学方法,
我们将探索与NMDAR和ENaC之间相互作用相关的分子信号传导,
引起血管舒张。目的III:观察NMDAr对大鼠血压和肾脏的影响,
血流动力学我们将评估NMDA对血压和肾脏血流动力学的作用,
使用NMDAr抑制剂的ENaC通道功能获得性小鼠(Liddle综合征)。的目的和假设
该提案与促进心脏和血液疾病预防和治疗的NHLBI提案一致
通过刺激对疾病原因的基本发现来治疗疾病。罗梅罗博士的发展计划
在这些资助年包括:1)通过巩固微灌注增加他的研究经验,
技术和探索两个新的领域有关的电生理学和蛋白质组学,同时扩大他的
批判性思维和实验室管理技能; 2)增加他的教学和指导经验; 3)
进一步发展他的沟通技巧和出版记录。罗梅罗博士将由沃尔博士指导,
主要导师以及伊顿博士和胡佛博士作为共同导师。此外,一个咨询委员会将
支持这项计划的发展。罗梅罗博士的职业目标是成为一名独立资助的
美国一所高排名大学的首席研究员,研究肾脏血流动力学和肾小管转运
相互作用及其在高血压中的作用。这个职业发展计划将完全在埃默里大学执行
USA.
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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Cesar Andres Romero其他文献
Cesar Andres Romero的其他文献
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{{ truncateString('Cesar Andres Romero', 18)}}的其他基金
N-methyl-D-aspartate receptors (NMDAr) participates in renal hemodynamic regulation and blood pressure homeostasis
N-甲基-D-天冬氨酸受体(NMDAr)参与肾脏血流动力学调节和血压稳态
- 批准号:
10326856 - 财政年份:2021
- 资助金额:
$ 10.45万 - 项目类别:
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