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

• 批准号: 8648463
• 负责人: Adam J Case
• 金额: $ 5.33万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/8648463
• 关键词: Adoptive Transfer; Americas; Angiotensin II; Antioxidants; Attenuated; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cells; Collection; Communication; Data; Development; Disease; Electron Transport; Environment; Enzymes; Failure; Family; Free Radicals; Gene Expression; Gene Proteins; Heart Rate; Hypertension; Immune; Immune system; Inflammatory; Infusion procedures; Lead; Lymphocyte Activation; Maintenance; Manganese Superoxide Dismutase; Mediating; Mitochondria; Modeling; Molecular; Mus; NADPH Oxidase; Neuraxis; Neurons; Oxidation-Reduction; Pathogenesis; Pathologic; Pharmacologic Substance; Physiological; Production; Reactive Oxygen Species; Regulation; Research; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Smooth Muscle Myocytes; Source; Specificity; Stimulus; Superoxides; System; T-Lymphocyte; Technology; Testing; Time; antioxidant therapy; base; cell type; cellular targeting; cytokine; effective therapy; extracellular; genetic manipulation; in vivo; insight; mouse model; neurogenic hypertension; novel; overexpression; pressure; protein expression; public health relevance; second messenger; therapy design; transcription factor

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）：该项目将研究线粒体超氧化物（O 2？ - ）在T-淋巴细胞中其在高血压发病机理中激活的影响。活性氧，主要是O 2？ - 已被阐明为血管紧张素II（ANGII）依赖性高血压中的关键分子中间体。最近，免疫系统，尤其是T淋巴细胞激活，已通过加剧促炎性环境，在AngII介导的高血压中被证明是因果关系。但是，o 2？ - 在介导血管内刺激的T淋巴细胞中细胞内信号传导途径中的作用尚不清楚。在其他细胞类型中，线粒体已被确定为Angii诱导的O2？ - 产生的关键来源，是线粒体量化的O2的过表达？我们的初步数据表明，在Angii刺激的T淋巴细胞中，线粒体也是O2的来源。在此，我们假设线粒体生产的O2？ - 介导细胞内的T淋巴细胞信号传导，导致它们在Angii介导的高血压期间的激活并增强细胞因子的产生。在特定的目标1中，我们将研究用AngII刺激的小鼠初级T淋巴细胞中线粒体O2的因果来源。有希望的候选源包括NADPH氧化酶（NOX）酶，MNSOD和电子传输链。特定的目标2将检查AngII如何在T淋巴细胞中进行信号转导。使用微阵列和细胞因子阵列技术，我们将对信号转导途径进行全面分析，我们将获得特定的第二使者和转录因子以进一步验证。我们将利用使用MNSOD缺陷和过表达MNSOD的小鼠模型来了解线粒体O2？ - 对AngII介导的T淋巴细胞内信号传导的贡献。最后，特定目标3将检查体内T淋巴细胞中线粒体O2改变的生理参数。通过检查具有扰动的线粒体O2的小鼠中的平均动脉压（MAP）和心率（HR）？ - 特别是在T-淋巴细胞中，我们将在体内端点获得直接连接到高血压。总体而言，该项目将进一步理解免疫系统对高血压的贡献，该贡献的基于氧化还原的机制，并为药物治疗提供了潜在的新靶标，这些目标目前未被确认在高血压中。