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.

抽象的 在国际上，高血压是死亡率的主要单一风险因素。但是，超过90％ 高血压患者，原因是未知的。迫切需要了解背后的机制 高血压的起源是使新疗法的发展。连接管胶质细胞 反馈（CNTGF）是一种上皮钠通道（ENAC）依赖性的肾脏反馈机制 通过诱导的血管舒张，在某些生理情况下促进钠排泄。它一直 以前证明，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 目的是探索肾脏中血管舒张受损的后果，以作为高血压的原因 并制定一个程序，以彻底了解人类高血压的某些原因。主 假设是NMDAR介导的血管舒张和CNTGF的机制密切相关，并且 这些生物学途径的损害会诱导高血压。该假设将通过 遵循特定目标。目的I：确定NMDAR诱导的肾血管舒张的机理。我们将 评估NMDAR在CNTGF诱导的血管舒张中在体外使用微灌注的作用，并使用体内使用 NMDAR NR2C无效小鼠。 AIM 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与ENAC之间相互作用相关的分子信号传导 诱导血管舒张。 AIM III：测试NMDAR对血压和肾脏的影响 血液动力学。我们将通过治疗NMDA评估NMDA在血压和肾脏血液动力学方面的作用 NMDAR抑制剂的ENAC通道增益功能小鼠（Liddle综合征）。目的和假设 该提议与NHLBI的提案保持一致，促进了心脏和血液的预防和治疗 通过刺激有关疾病原因的基本发现，疾病。罗梅罗博士的发展计划 在这些资金的年份中包括：1）通过合并微灌注来增加他的研究经验 技术并探索与电生理学和蛋白质组学有关的两个新领域，同时扩展他的 批判性思维和实验室管理技能； 2）增加他的教学和心理经验； 3） 进一步发展他的沟通技巧和出版记录。罗梅罗博士将以沃尔博士为指导 首席导师以及伊顿博士和胡佛博士担任联席会员。此外，咨询委员会将 支持该计划的制定。罗梅罗博士的职业目标是成为一个独立资助的 一所高度排名的美国大学的首席研究员，研究肾脏血液动力学和管状运输 相互作用及其在高血压中的作用。该职业发展计划将完全在Emory执行 美国佐治亚州大学。