Renal Endothelin-1: Control of Sodium Excretion and Blood Pressure

肾内皮素-1：控制钠排泄和血压

• 批准号: 8299352
• 负责人: Maria Marcela Herrera
• 金额: $ 8.85万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-15 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8299352
• 关键词: Academic Medical Centers; Achyrocline; Adenoviruses; Animal Model; Animals; Asses; Autacoids; Blood Pressure; Blood flow; Cardiovascular Diseases; Cell physiology; Cessation of life; Commit; Conscious; Control Animal; Defect; Development; Development Plans; Diet; Dietary intake; Dinoprostone; Disease; Distal; Endothelin; Endothelin-1; Epithelial; Excision; Excretory function; Foundations; Genes; Genetic; Genetic Techniques; Goals; Hypertension; In Vitro; Individual; Intake; Kidney; Kidney Diseases; Knockout Mice; Lead; Measures; Mediating; Mediator of activation protein; Mentors; Methods; Molecular Genetics; Mus; Natriuresis; Nephrons; PTGS2 gene; Pathogenesis; Pathway interactions; Patients; Peptides; Phase; Physiological; Physiology; Play; Production; Prostaglandin-Endoperoxide Synthase; Protein Isoforms; Public Health; Quality of life; Rectum; Regulation; Relative (related person); Research; Research Personnel; Role; Signal Transduction; Sodium; Sodium Chloride; Solid; Stroke; Structure; Structure of ascending limb of Henle' s loop; System; Techniques; Technology; Testing; Thick; Tissues; Training; Transgenic Animals; Tubular formation; Video Microscopy; autocrine; base; blood pressure regulation; career; career development; cell type; defined contribution; feeding; improved; in vivo; innovation; insight; interdisciplinary approach; interstitial cell; kidney medulla; lipid mediator; mature animal; novel strategies; paracrine; post-doctoral training; prevent; programs; receptor; response; salt intake; salt sensitive; saluretic; tool

DESCRIPTION (provided by applicant): High blood pressure is a major public health problem worldwide leading to cardiovascular disease and death. The kidneys play a critical role in maintaining normal blood pressure by increasing salt excretion when dietary intake is elevated. Inappropriate salt retention by the kidneys results in hypertension. Understanding the mechanisms by which the kidneys eliminate excess salt will clarify the causes of hypertension and identify new approaches for treatment, extending patient's lives and improving their quality of life. Recent studies have shown that high salt intake increases production of the small peptide endothelin-1 within the kidney; however, its role in stimulating salt excretion in vivo is unknown. The overall goal of this proposal is to investigate how endothelin-1 causes the kidney to eliminate more salt during high salt feeding. Overall hypotheses to be tested are: 1) when dietary salt is elevated, endothelin-1 derived from the nephron acts as an autacoid, inhibiting salt reabsorption and promoting natriuresis; and 2) endothelin-1 also functions as a paracrine factor that acts on adjacent medullary interstitial cells to stimulate medullary blood flow and facilitate sodium excretion. Both mechanisms are crucial for high salt-induced natriuresis, and defects in this system will lead to salt retention and hypertension. These hypotheses will be tested using animals in which expression of individual genes is eliminated only in certain types of cells in the kidney, employing novel approaches that combine in vivo and in vitro technology. This application provides the foundation for a career development plan for Dr. Marcela Herrera, a cell/physiology-trained post-doctoral fellow committed to a research career in kidney disease and hypertension. The applicant will be mentored by Dr. Thomas Coffman at Duke University Medical Center, who will train the PI in generating transgenic animal models and using in vivo physiological techniques to study them. This proposal has been structured to provide complementary and substantive training opportunities. The applicant will gain expertise in mouse genetics, producing transgenic animals, and in vivo physiology. This will provide a solid basis for the trainee to develop a multi-disciplinary program of research using physiological, cellular/molecular, and genetic techniques to achieve her goal of becoming an independent investigator.

描述（由申请人提供）：高血压是全球范围内导致心血管疾病和死亡的主要公共卫生问题。当饮食摄入量增加时，肾脏通过增加盐的排泄在维持正常血压方面起着关键作用。肾脏不适当的盐潴留会导致高血压。了解肾脏消除过量盐的机制将澄清高血压的原因，并确定新的治疗方法，延长患者的生命并提高他们的生活质量。最近的研究表明，高盐摄入增加了肾脏内小肽内皮素-1的产生;然而，其在体内刺激盐排泄的作用尚不清楚。 该提案的总体目标是研究内皮素-1如何导致肾脏在高盐喂养期间消除更多的盐。待检验的总体假设为：1）当膳食盐升高时，源自肾单位的内皮素-1充当自泌素，抑制盐重吸收并促进尿钠排泄;和2）内皮素-1还充当旁分泌因子，其作用于邻近的髓质间质细胞以刺激髓质血流并促进钠排泄。这两种机制对于高盐诱导的尿钠排泄都是至关重要的，该系统的缺陷将导致盐潴留和高血压。这些假设将使用动物进行测试，在这些动物中，单个基因的表达仅在肾脏中的某些类型的细胞中被消除，采用结合联合收割机体内和体外技术的新方法。该应用程序为Marcela Herrera博士的职业发展计划提供了基础，Marcela Herrera博士是一名细胞/生理学培训的博士后研究员，致力于肾脏疾病和高血压的研究事业。申请人将由杜克大学医学中心的托马斯科夫曼博士指导，他将培训PI生成转基因动物模型并使用体内生理学技术对其进行研究。这项建议的结构是为了提供补充性和实质性的培训机会。申请人将获得小鼠遗传学，生产转基因动物和体内生理学方面的专业知识。这将为受训者提供坚实的基础，利用生理学，细胞/分子和遗传技术开发多学科研究计划，以实现成为独立调查员的目标。