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: 10555201
• 负责人: Cesar Andres Romero
• 金额: $ 10.45万
• 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/10555201
• 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); Epithelium; 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; Perfusion; 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。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。罗梅罗医生的长期 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， 技术并探索与电生理学和蛋白质组学相关的两个新领域，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.