Redox Regulation of T-lymphocytes in Sympathoexcitation-associated Hypertension

 描述（由申请人提供）：项目总结高血压是心血管疾病的主要原因，心血管疾病是美国死亡的主要原因。目前的高血压药物已被证明不足以控制疾病，因为数百万患者保持不受控制的高血压1。因此，阐明新的治疗靶点对于最终完全治疗这种多维疾病至关重要。免疫系统，特别是T淋巴细胞活化，通过加剧促炎环境而导致高血压的发病机制2 -7。然而，调节T淋巴细胞中这一过程的细胞外刺激和细胞内机制仍不清楚。此外，线粒体产生的超氧化物（O2●-）已被阐明为高血压过程中各种细胞类型的关键分子中间体。我们的初步数据表明，8-14去甲肾上腺素驱动的高血压小鼠的T淋巴细胞中线粒体O2●-增加，表明免疫系统可能另外利用这种反应性分子作为关键的细胞内信号中间体。本课题旨在探讨T淋巴细胞线粒体O2●-在高血压发病中的作用。在本项目的指导阶段，将研究O2●-的分子来源以及T淋巴细胞中改变的线粒体O2●-对血流动力学参数的贡献。在这个指导阶段，我将通过学习与心血管和分子生理学相关的技术来扩展我广泛的氧化还原生物学经验，如细胞呼吸测量，无线电遥测利用，神经记录，遗传动物操作和一系列分子生物学分析。同时，我将继续我的专业发展，服务于国家委员会，指导初级学员，参加期刊俱乐部，研讨会和课程，手稿写作和审查，并由学员咨询委员会进行半年一次的评估。该项目的独立阶段将使我能够在心血管生理学领域建立自己的地位，我将通过研究线粒体O2●-如何调节核基因信号传导、调节和表观遗传景观，特别是负性T淋巴细胞调节基因PD-1，继续研究高血压期间的T淋巴细胞。总的来说，这个项目将通过持续的技术，智力和专业培训来解决在学术研究机构建立独立的心血管研究实验室所需的特定培训不足，同时利用和提高我目前的专业知识。

 DESCRIPTION (provided by applicant): PROJECT SUMMARY Hypertension is a primary contributor to cardiovascular disease, which is the leading cause of mortality in America. Current medications for hypertension have proven to be insufficient in the management of the disease, as millions of patients retain uncontrolled high blood pressure1. With this, the elucidation of novel therapeutic targets is essential for the eventual complete treatment of this multidimensional disease. The immune system, particularly T-lymphocyte activation, contributes to the pathogenesis of hypertension by exacerbating a pro-inflammatory environment2-7. However, the extracellular stimuli and intracellular mechanisms regulating this process in T-lymphocytes remain unclear. Furthermore, mitochondrial produced superoxide (O2●-) has been elucidated as a key molecular intermediate in various cell types during hypertension . Our preliminary data suggest mitochondrial O2●- is increased in T-lymphocytes from 8-14 norepinephrine-driven hypertensive mice suggesting the immune system may additionally utilize this reactive molecule as a critical intracellular signaling intermediate. This project will investigate the influence of mitochondrial O2●- in T-lymphocytes during the pathogenesis of hypertension. Molecular sources of O2●- and the contribution of altered mitochondrial O2●- specifically in T- lymphocytes to hemodynamic parameters will be investigated during the mentored phase of this project. In this mentored phase, I will expand upon my extensive redox biology experience by learning techniques related to cardiovascular and molecular physiology such as cellular respiration measurements, radiotelemetry utilization, nerve recording, genetic animal manipulation, and an array of molecular biology assays. Concurrently, I will continue my professional development by serving on national committees, mentoring junior trainees, participating in journal clubs, seminars, and coursework, manuscript writing and reviewing, and having semiannual evaluations by a trainee advisory committee. The independent phase of this project will allow me to establish myself in the field of cardiovascular physiology where I will continue investigations in T- lymphocytes during hypertension by examining how mitochondrial O2●- modulates nuclear gene signaling, regulation, and epigenetic landscapes specifically of the negative T-lymphocyte regulatory gene PD-1. Collectively, this project will address specific training deficits needed to establish an independent cardiovascular research laboratory at an academic research institution by continued technical, intellectual, and professional training, while at the same time employing and enhancing my current expertise.