Regulation of Mitochondrial Redox Systems in T-lymphocytes During Hypertension

高血压期间 T 淋巴细胞线粒体氧化还原系统的调节

基本信息

  • 批准号:
    8648463
  • 负责人:
  • 金额:
    $ 5.33万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-07-01 至 2015-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): This project will investigate the influence of mitochondrial superoxide (O 2?-) in T-lymphocytes on their activation in the pathogenesis of hypertension. Reactive oxygen species, mainly O 2 ?-, have been elucidated as key molecular intermediates in angiotensin II (AngII)-dependent hypertension. Recently, the immune system, particularly T-lymphocyte activation, has proven causal in AngII-mediated hypertension by exacerbating a pro- inflammatory environment; however, the role of O 2 ?- in mediating intracellular signaling pathways in AngII-stimulated T-lymphocytes remains unclear. In other cell types, mitochondria have been identified as a key source of AngII-induced O2 ?- production, as over-expression of the mitochondrially-localized O2 ?- scavenging enzyme manganese superoxide dismutase (MnSOD) attenuates AngII-mediated O2?- flux. Our preliminary data suggest mitochondria are also a source of O2 ?- in AngII-stimulated T-lymphocytes. Herein, we hypothesize that mitochondrially-produced O2 ?- mediates intracellular T-lymphocyte signaling leading to their activation and enhanced production of cytokines during AngII-mediated hypertension. In Specific Aim 1, we will investigate a causal source of mitochondrial O2?- in mouse primary T-lymphocytes stimulated with AngII. Promising candidate sources include the NADPH oxidase (NOX) enzymes, MnSOD, and the electron transport chain. Specific Aim 2 will examine how AngII carries out signal transduction in T-lymphocytes. Using microarray and cytokine array technology, we will perform a comprehensive analysis of signal transduction pathways, which we will garner specific second messengers and transcription factors to further validate. We will employ the use of MnSOD-deficient and MnSOD-overexpressing mouse models to understand the contribution of mitochondrial O2 ?- to AngII-mediated T-lymphocyte intracellular signaling. Finally, Specific Aim 3 will examine physiological parameters of altered mitochondrial O2 ?- in T-lymphocytes in vivo. By examining mean arterial pressure (MAP) and heart rate (HR) in mice with perturbed mitochondrial O2 ?- specifically in T-lymphocytes, we will obtain in vivo endpoints that will provide a direct connection to hypertension. Overall, this project will further the understanding of the immune system contribution to hypertension, the redox based mechanisms underlying this contribution, and provide potential new targets for pharmaceutical therapy that are currently unacknowledged in hypertension.
描述(由申请人提供):本项目将研究线粒体超氧化物(O2?-)在高血压的发病机制中,T淋巴细胞对其活化的影响。活性氧,主要是O2?-,已被阐明为血管紧张素II(AngII)依赖性高血压的关键分子中间体。最近,免疫系统,特别是T淋巴细胞活化,已被证明是血管紧张素II介导的高血压的原因,加剧了促炎症环境;然而,O2?在AngII刺激的T淋巴细胞中介导细胞内信号传导途径的作用尚不清楚。在其他细胞类型中,线粒体已被确定为AngII诱导的O2?-生产,作为过度表达的神经本地化的O2?-清除酶锰超氧化物歧化酶(MnSOD)减弱血管紧张素II介导的O2?-通量我们的初步数据表明线粒体也是O2?血管紧张素II刺激的T淋巴细胞。在此,我们假设,尿道产生的O2?-在AngII介导的高血压期间,介导细胞内T淋巴细胞信号传导,导致其活化和细胞因子的产生增强。在具体目标1中,我们将研究线粒体O2?- 在用AngII刺激的小鼠原代T淋巴细胞中。有希望的候选来源包括NADPH氧化酶(NOX)酶,MnSOD和电子传递链。具体目标2将研究AngII如何在T淋巴细胞中进行信号转导。利用微阵列和细胞因子阵列技术,我们将对信号转导通路进行全面分析,我们将获得特定的第二信使和转录因子,以进一步验证。我们将采用MnSOD缺陷和MnSOD过表达小鼠模型来了解线粒体O2?血管紧张素II介导的T淋巴细胞胞内信号。最后,具体目标3将检查改变线粒体O2?在体内T淋巴细胞中。通过检测线粒体O2?特别是在T淋巴细胞中,我们将获得与高血压直接相关的体内终点。总的来说,该项目将进一步了解免疫系统对高血压的贡献,这种贡献背后的氧化还原机制,并为目前未被承认的高血压药物治疗提供潜在的新靶点。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Adam J Case其他文献

Disruption of Mitochondrial Superoxide Flux Causes Abnormal Heme Synthesis and Hemoglobin Gene Regulation in Erythroid Precursor Cells
  • DOI:
    10.1016/j.freeradbiomed.2012.10.035
  • 发表时间:
    2012-11-01
  • 期刊:
  • 影响因子:
  • 作者:
    Adam J Case;Joshua M Madsen;David G Motto;David K Meyerholz;Frederick E Domann
  • 通讯作者:
    Frederick E Domann
A Novel Role for Mitochondrial Superoxide in the Development of Erythropoietic Protoporphyria
  • DOI:
    10.1016/j.freeradbiomed.2010.10.234
  • 发表时间:
    2010-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    Adam J Case;Frederick E. Domann
  • 通讯作者:
    Frederick E. Domann
Conditional Knockout of <em>Sod2</em> in Murine Hepatocytes Disrupts Epigenetic Control of Gene Expression
  • DOI:
    10.1016/j.freeradbiomed.2010.10.351
  • 发表时间:
    2010-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    Anthony R Cyr;Adam J Case;Gaowei Mao;Frederick E Domann
  • 通讯作者:
    Frederick E Domann

Adam J Case的其他文献

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{{ truncateString('Adam J Case', 18)}}的其他基金

Neuroimmune dynamics involved in the pathogenesis of hypertension after psychological trauma
神经免疫动力学参与心理创伤后高血压的发病机制
  • 批准号:
    10450810
  • 财政年份:
    2021
  • 资助金额:
    $ 5.33万
  • 项目类别:
Neuroimmune dynamics involved in the pathogenesis of hypertension after psychological trauma
神经免疫动力学参与心理创伤后高血压的发病机制
  • 批准号:
    10269653
  • 财政年份:
    2021
  • 资助金额:
    $ 5.33万
  • 项目类别:
Neuroimmune dynamics involved in the pathogenesis of hypertension after psychological trauma
神经免疫动力学参与心理创伤后高血压的发病机制
  • 批准号:
    10629301
  • 财政年份:
    2021
  • 资助金额:
    $ 5.33万
  • 项目类别:
Redox Regulation of T-lymphocytes in Sympathoexcitation-associated Hypertension
交感神经兴奋相关性高血压中 T 淋巴细胞的氧化还原调节
  • 批准号:
    9291573
  • 财政年份:
    2015
  • 资助金额:
    $ 5.33万
  • 项目类别:

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