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
• 负责人: Cesar Andres Romero
• 金额: $ 10.35万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10326856
• 关键词: Address; Advisory Committees; Agonist; Amino Acids; Animals; Apical; Area; Arteries; Biological; Blood Pressure; Calcium; Calcium Channel; Calpain; Cardiovascular Diseases; Cells; Communication; Critical Thinking; Data; Development; Development Plans; Dialysis procedure; Diet; Disease; Duct (organ) structure; Educational process of instructing; Electrophysiology (science); Epithelial; Excretory function; Feedback; Functional disorder; Funding; Genetic; Genetic Transcription; Glomerular Filtration Rate; Glutamates; Glycine; Goals; Heart Diseases; Hematological Disease; Human; Hypertension; Imaging Techniques; Impairment; In Vitro; Individual; International; Kidney; Knockout Mice; Label; Laboratories; Liddle syndrome; Mediating; Mentors; Molecular; Mus; Myocardial Infarction; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; National Heart, Lung, and Blood Institute; Pathway interactions; Patients; Peptide Hydrolases; Physiological; Prevention; Principal Investigator; Proteomics; Publications; Regulation; Research; Resistance; Risk Factors; Role; Signal Transduction; Sodium; Sodium Chloride; Spectrum Analysis; Stroke; Techniques; Testing; Tubular formation; Universities; Urine; Vasodilation; antagonist; arteriole; benzamil; blood pressure elevation; blood pressure regulation; cardiovascular risk factor; career; career development; confocal imaging; epithelial Na+ channel; experience; falls; hemodynamics; hypertensive; in vivo; inhibitor; mRNA Expression; mortality; normotensive; novel therapeutics; programs; protein protein interaction; skills; therapeutic development

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。迫切需要了解背后的机制 高血压的起源使新疗法的开发成为可能。连接小管-肾小球 反馈(CNTGF)是一种依赖上皮钠通道(ENaC)的肾脏反馈机制， 在某些生理情况下通过诱导血管扩张来促进钠的排泄。一直以来 先前证明，由N-甲基-D-天冬氨酸受体(NMDAR)介导的氨基酸可以 诱导肾血管扩张。NMDAR诱导的血管扩张机制尚不清楚。罗梅罗医生的长期 目的是探讨肾脏血管扩张受损作为高血压的一个原因的后果。 并开发一个程序，彻底了解人类高血压的一些原因。主 假设NMDAR介导的血管扩张机制与CNTGF密切相关，并且 这些生物通路的损伤会导致高血压。这一假设将通过 遵循特定的目标。目的：探讨NMDAR扩张肾血管的作用机制。我们会 用微灌注法和体内实验评价NMDAR在CNTGF诱导的血管扩张中的作用 NMDAR NR2C基因缺失小鼠。目的II：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相互作用相关的分子信号转导 诱导血管扩张。目的III：检测NMDAR对血压和肾脏的影响 血流动力学。我们将通过治疗来评估NMDA对血压和肾脏血流动力学的作用。 使用NMDAR抑制剂的ENAC通道功能增益小鼠(利德尔综合征)。的目标和假设 这项建议与NHLBI促进心脏和血液预防和治疗的建议一致 通过刺激对疾病原因的基本发现来防治疾病。罗梅罗博士的发展计划 在这些资助年中包括：1)通过巩固微灌注来增加他的研究经验 技术和在扩展HIS的同时探索与电生理学和蛋白质组学有关的两个新领域 批判性思维和实验室管理技能；2)增加教学和指导经验；3) 进一步培养他的沟通能力和出版记录。罗梅罗博士将由沃尔博士作为一名 首席导师以及伊顿博士和胡佛博士作为共同导师。此外，还将设立一个咨询委员会 支持这一计划的发展。罗梅罗博士的职业目标是成为一名独立资助的 美国一所排名很高的大学的首席研究员，研究肾脏血流动力学和肾小管运输 相互作用及其在高血压中的作用。这项职业发展计划将完全在埃默里执行 美国佐治亚州大学