The Effect of Salt on T Cell Function in Hypertension

盐对高血压患者 T 细胞功能的影响

基本信息

  • 批准号:
    9138616
  • 负责人:
  • 金额:
    $ 1.82万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-09-01 至 2017-05-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Hypertension is a leading cause of cardiovascular disease morbidity and mortality and is a key contributor to myocardial infarction, stroke, heart failure and chronic kidney disease. The prevalence of hypertension reaches 30% of adults in the United States alone. We have put forth evidence in the past few decades suggesting that hypertension is an inflammatory disease mediated by cells of the innate and adaptive immune systems, specifically by IL17-producing T cells. In addition, many studies have linked dietary salt intake to hypertension. In preliminary studies, we and others have shown that excess salt promotes differentiation of IL17A-producing CD4+ (Th17) and CD8+ (Tc17) cells. In response to salt, these cells upregulate the osmosensitive transcription factor, TonEBP (NFAT5) and one of its downstream targets, the salt-sensing kinase 1 (SGK1). The potential importance of SGK1 in modulating T cell function is interesting as it directly connects salt to inflammation. However, th mechanism by which salt acts to affect the progression of hypertension is unknown. Additionally, a subset of T cells possesses voltage-gated sodium channels. We have preliminary data showing that the Na+ channel SCN5A is upregulated in CD4+ and CD8+ T cells when these cells are exposed to Th17 polarizing cytokines and salt. Therefore, I hypothesize that SGK1 is essential to the ability of T cells to mediate hypertension by regulating SCN5A; and increasing the pathogenicity of the resultant Th17/Tc17 cells. To test this hypothesis I first plan to determine whether T cell SGK1 is necessary for the hypertensive and inflammatory response to angiotensin II and DOCA-salt by genetically deleting SGK1 in all T cells in mice. To do this, we have generated a colony of mice that are CD4cre/SGK1fl/fl. We will use these mice to determine if loss of SGK1 in T cells results in lowered blood pressure, increased renal/vascular function and decreased renal/vascular inflammation compared to control mice when exposed to hypertensive stimuli. Next I will determine if SCN5A is regulated by SGK. To do this, I will conduct pulse chase analyses, RT-PCR and phospho-flow on polarized T cells from wild type mice (C57BL/6J) or from CD4cre/SGK1fl/fl mice. Finally, I will determine if SCN5A activity is required for Th17/Tc17 cell pathogenicity. I will knock down SCN5A with siRNA and measure the amount of IL17A by RT-PCR after the cells are polarized with salt and Th17 cytokines. I will also compare sodium currents measured by whole cell patch clamping in T cells from hypertensive and normotensive mice and humans. In addition, I will quantify the membrane potential and the amount of sodium entering T cells that have been polarized with Th17 cytokines and then shocked with excess salt. Completion of these studies will ideally lead to the identification of novel therapeutic targets to treat hypertension.


项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Allison Elizabeth Norlander其他文献

Allison Elizabeth Norlander的其他文献

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{{ truncateString('Allison Elizabeth Norlander', 18)}}的其他基金

PGI2 restrains immunopathogenesis in hypertension
PGI2 抑制高血压的免疫发病机制
  • 批准号:
    10731402
  • 财政年份:
    2023
  • 资助金额:
    $ 1.82万
  • 项目类别:
PGI2 restrains immunopathogenesis in hypertension
PGI2 抑制高血压的免疫发病机制
  • 批准号:
    10282751
  • 财政年份:
    2021
  • 资助金额:
    $ 1.82万
  • 项目类别:
PGI2 restrains immunopathogenesis in hypertension
PGI2 抑制高血压的免疫发病机制
  • 批准号:
    10447208
  • 财政年份:
    2021
  • 资助金额:
    $ 1.82万
  • 项目类别:
The Effect of Salt on T Cell Function in Hypertension
盐对高血压患者 T 细胞功能的影响
  • 批准号:
    8908297
  • 财政年份:
    2015
  • 资助金额:
    $ 1.82万
  • 项目类别:

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