Contribution of Renal Tubule Insulin Receptor on Proximal Tubule Sodium Transport and Hypertension int he Metabolic Syndrome

肾小管胰岛素受体对近小管钠转运和代谢综合征高血压的作用

• 批准号: 10240479
• 负责人: Jonathan Nizar
• 金额: $ 15.11万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10240479
• 关键词: Acute; Address; Affect; American; Animals; Apical; Area; Basic Science; Bioinformatics; Blood; Blood Pressure; Blood Volume; Cells; Chronic; Data; Diabetes Mellitus; Diet; Disease; Dose; Environment; Epithelial Cells; Essential Hypertension; Excretory function; Faculty; Feedback; Financial cost; Future; Genes; Glucose; Health; Health Care Costs; Hormones; Hyperinsulinism; Hypertension; Impairment; Individual; Infusion procedures; Insulin; Insulin Receptor; Insulin Resistance; Kidney; Knockout Mice; Knowledge; Learning Skill; Measures; Medical; Mentors; Metabolic syndrome; Modeling; Molecular Biology; Mus; Natriuresis; Nephrology; Obesity; Operative Surgical Procedures; Pathogenesis; Patients; Pattern; Phase; Physicians; Physiology; Play; Receptor Activation; Receptor Signaling; Recording of previous events; Regulation; Renal tubule structure; Research; Risk; Role; Scientist; Sodium; Surface; System; Techniques; Testing; Tissues; Training; Tubular formation; United States; Wild Type Mouse; Work; Zucker Rats; career; insulin signaling; interest; kidney dysfunction; mouse model; novel; pressure; receptor expression; response; salt sensitive; sequencing platform; societal costs; tool; trafficking; transcriptome; transcriptome sequencing

Project Summary / Abstract Hypertension in patients with Metabolic Syndrome incurs a large financial, societal, and health cost in the United States. Despite several lines of evidence that hypertension in the Metabolic Syndrome has a distinct cause from idiopathic (essential) hypertension, this cause is not known and patients are treated empirically. Contributions from many labs over the last 30 years have supported the hypothesis that enhanced insulin signaling in the kidney plays a critical role in the pathogenesis of this disease. The Applicant's preliminary data confirms the hypothesis that insulin action in the kidney contributes to hypertension in a mouse model of Metabolic Syndrome and suggests that proximal tubular sodium transport may be increased, expanding blood volume, and increasing blood pressure. The Applicant has (1) characterized: a mouse model to study the intersection of the kidney, blood pressure, and Metabolic Syndrome and (2) generated a novel inducible tubule insulin receptor knockout mouse to study the contribution of insulin receptor signaling to sodium transport and blood pressure. In addition to the Applicant's contributions, the mentoring and scientific environment make him an ideal candidate to develop independence in renal physiology research addressing this important question. Here, the Applicant proposes three aims to study the contribution of insulin receptor signaling in the Metabolic Syndrome to acute pressure natriuresis (Aim 1), to regulators of proximal tubule sodium transporter activity in response to acute and chronic hypertension (Aim 2), and to patterns within the proximal tubule epithelial cell transcriptome generated by insulin receptor signaling, the Metabolic Syndrome, or both (Aim 3). Successful completion of these aims will begin to bridge the gap in knowledge between the role of insulin in whole animal physiology and transporter activity and regulation in individual cells. In addition, through this training mechanism the Applicant will learn the skills to successfully conduct independent research in basic science nephrology.

项目概要/摘要 代谢综合征患者的高血压会造成巨大的经济、社会和健康成本 美国。尽管有多项证据表明代谢综合征中的高血压具有明显的 特发性（原发性）高血压引起，该原因尚不清楚，患者需根据经验进行治疗。 过去 30 年许多实验室的贡献支持了这样的假设：增强胰岛素 肾脏信号传导在这种疾病的发病机制中起着至关重要的作用。申请人的初步资料 证实了以下假设：在小鼠模型中，肾脏中的胰岛素作用导致高血压 代谢综合征并表明近端肾小管钠转运可能增加，从而扩大血液 容量和血压升高。申请人具有（1）特征：用于研究 肾脏、血压和代谢综合征的交叉点，(2) 产生了一种新型的诱导小管 胰岛素受体敲除小鼠研究胰岛素受体信号传导对钠转运的贡献 血压。除了申请人的贡献之外，指导和科学环境也使他 是发展肾脏生理学研究独立性以解决这一重要问题的理想人选。 在此，申请人提出了三个目标来研究胰岛素受体信号传导在代谢中的贡献 急性压力尿钠综合症（目标 1），近曲小管钠转运蛋白活性的调节因子 对急性和慢性高血压的反应（目标 2）以及近曲小管上皮细胞内的模式 由胰岛素受体信号传导、代谢综合征或两者产生的转录组（目标 3）。成功的 这些目标的完成将开始弥合胰岛素在整个动物中的作用之间的知识差距 单个细胞的生理学和转运蛋白活性和调节。另外，通过本次培训 申请人将学习成功进行基础科学独立研究的技能的机制 肾脏病学。