Renal Mechanisms in Blood Pressure Control

血压控制中的肾脏机制

基本信息

  • 批准号:
    8726472
  • 负责人:
  • 金额:
    $ 187.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-09-01 至 2018-06-30
  • 项目状态:
    已结题

项目摘要

The integrating theme and unifying hypothesis of this PPG centers on the concept that H202 production in the renal outer medulla (CM) plays a dominant role in the development of salt-sensitive hypertension. Studies in this PPG will use Dahl salt-sensitive (SS) rats to examine physiological mechanisms and molecular pathways underlying salt-sensitive hypertension; it does not focus on the generic aspects of this disease. This rat model recapitulates many aspects of human salt-sensitive hypertension and demonstrates disease phenotypes which are very similar to those observed in African Americans. Project 1 explores the role of the medullary thick ascending limb (mTAL) and tests the hypothesis that increased salt intake leads to greater mTAL NaCI delivery resulting in excess production of H202 in SS rats as amplified by a greater expression of the p67phox subunit of NADPH oxidase. It is proposed that this results in greater H202 diffusion into the interstitial space thereby constricting vasa recta and reducing medullary perfusion. Project 2 hypothesizes that the initials rise of arterial pressure following an increase in salt intake leads to the infiltration of T-cells in the kidney which exaggerates salt-sensitive hypertension and renal disease by increasing H202 and cytokines. The resulting T-lymphocyte infiltration into the kidney, we propose, is importanfiy influenced by Sh2b3, a gene recently identified by GWAS to be associated with human hypertension. Project 3 hypothesizes that a newly discovered pathway of H202 production related to cellular metabolism contributes importantly to the development and maintenance of hypertension in SS rats. Specifically, fumarase insufficiency in SS rats results in an increase of fumaric acid and glycolytic activity which stimulates H202 production and contributes to the salt-induced hypertension. These conceptually unique hypotheses combined with novel technological tools will advance our understanding of the molecular and physiological mechanisms underlying salt-sensitive hypertension that remain largely unclear. This highly integrated and collaborative program of three projects is supported by an Administrative Core A, the Biochemistry/Microscopy Core B, and Genetic Model Tracking and Monitoring Core C.
该 PPG 的整合主题和统一假设集中在以下概念上:肾外髓质 (CM) 中 H2O2 的产生在盐敏感性高血压的发生中起主导作用。 该 PPG 的研究将使用 Dahl 盐敏感(SS)大鼠来检查盐敏感高血压的生理机制和分子途径;它不关注这种疾病的一般方面。该大鼠模型概括了人类盐敏感性高血压的许多方面,并展示了与非裔美国人中观察到的疾病表型非常相似的疾病表型。项目 1 探讨了髓质厚升肢 (mTAL) 的作用,并测试了这样的假设:增加盐摄入量会导致更多的 mTAL NaCl 输送,从而导致 SS 大鼠中 H2O2 产生过量,并通过 NADPH 氧化酶 p67phox 亚基的更大表达而放大。据认为,这导致更多的H 2 O 2 扩散到间隙空间中,从而收缩直肠血管并减少髓质灌注。项目 2 假设盐摄入量增加后动脉压的初始升高会导致肾脏中 T 细胞的浸润,从而通过增加 H2O2 和细胞因子来加剧盐敏感性高血压和肾脏疾病。我们认为,由此产生的 T 淋巴细胞浸润肾脏很大程度上受到 Sh2b3 的影响,Sh2b3 最近被 GWAS 鉴定为与人类高血压相关的基因。项目 3 假设新发现的与细胞代谢相关的 H2O2 产生途径对 SS 大鼠高血压的发生和维持有重要贡献。具体而言,SS大鼠中延胡索酶不足会导致延胡索酸和糖酵解活性增加,从而刺激H 2 O 2 产生并导致盐诱导的高血压。这些概念上独特的假设与新颖的技术工具相结合,将增进我们对盐敏感性高血压背后的分子和生理机制的理解,而这些机制目前尚不清楚。这个高度集成和协作的三个项目由行政核心 A、生物化学/显微镜核心 B 和遗传模型跟踪和监测核心 C 提供支持。

项目成果

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Allen W Cowley其他文献

Allen W Cowley的其他文献

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{{ truncateString('Allen W Cowley', 18)}}的其他基金

Experimental and computational analysis of mechanisms of mitochondrial-cellular ROS crosstalk in the kidney in salt-sensitive hypertension
盐敏感性高血压肾脏线粒体-细胞 ROS 串扰机制的实验和计算分析
  • 批准号:
    10529290
  • 财政年份:
    2021
  • 资助金额:
    $ 187.25万
  • 项目类别:
Experimental and computational analysis of mechanisms of mitochondrial-cellular ROS crosstalk in the kidney in salt-sensitive hypertension
盐敏感性高血压肾脏线粒体-细胞 ROS 串扰机制的实验和计算分析
  • 批准号:
    10321663
  • 财政年份:
    2021
  • 资助金额:
    $ 187.25万
  • 项目类别:
How Can Precision Medicine be Applied to Temporomandibular Disorders and its Comorbidities?
精准医学如何应用于颞下颌关节疾病及其合并症?
  • 批准号:
    9193954
  • 财政年份:
    2016
  • 资助金额:
    $ 187.25万
  • 项目类别:
Role of NOX4 In Kidney Function In Salt-Sensitive Hypertension
NOX4 在盐敏感性高血压肾功能中的作用
  • 批准号:
    8886255
  • 财政年份:
    2015
  • 资助金额:
    $ 187.25万
  • 项目类别:
Role of NOX4 In Kidney Function In Salt-Sensitive Hypertension
NOX4 在盐敏感性高血压肾功能中的作用
  • 批准号:
    9444474
  • 财政年份:
    2015
  • 资助金额:
    $ 187.25万
  • 项目类别:
Genetics and Epigenetics - Temporomandibular Disorders and Related Overlapping Co
遗传学和表观遗传学 - 颞下颌疾病和相关重叠疾病
  • 批准号:
    8785556
  • 财政年份:
    2014
  • 资助金额:
    $ 187.25万
  • 项目类别:
Renal Mechanisms in Blood Pressure Control
血压控制中的肾脏机制
  • 批准号:
    8866448
  • 财政年份:
    2013
  • 资助金额:
    $ 187.25万
  • 项目类别:
Renal Mechanisms in Blood Pressure Control
血压控制中的肾脏机制
  • 批准号:
    9304292
  • 财政年份:
    2013
  • 资助金额:
    $ 187.25万
  • 项目类别:
Renal Mechanisms in Blood Pressure Control
血压控制中的肾脏机制
  • 批准号:
    8548618
  • 财政年份:
    2013
  • 资助金额:
    $ 187.25万
  • 项目类别:
Comorbid Chronic Pain Conditions - Mechanisms, Diagnosis and Treatments
慢性疼痛共病 - 机制、诊断和治疗
  • 批准号:
    8203961
  • 财政年份:
    2011
  • 资助金额:
    $ 187.25万
  • 项目类别:

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