Neuro-Circulatory Function in Chronic Heart Failure

 描述(由申请人提供)：本计划项目资助(PPG)续期描述了一系列旨在回答有关慢性心力衰竭(CHF)交感神经兴奋机制的高度相关问题的实验。在这个PPG中，PI之间的互动已经有很长的历史了。我们对这一领域的文献做出了很大贡献，现在正在提议进行新的研究，更深入地探讨CHF中交感神经调节的起源。总体而言，这里描述的研究提供了CHF交感兴奋过程的部分分子基础。建议的研究与人类CHF进展的机制高度相关。在项目I中，重点将放在一种重要的抗氧化剂转录因子Nrf2及其胞质Teather，Keap1的作用上 在调节延髓头端腹外侧区神经元氧化应激中的作用。更重要的是，我们将证明Nrf2在细胞核内与NFkB竞争结合CREB结合蛋白，从而减少Nrf2与抗氧化反应元件(ARs)的结合。该项目的具体目标还将调查运动训练和血管紧张素转换酶2在调节Nrf2在CHF中的作用。项目二将侧重于室旁核在交感神经调节中的作用。拟议的研究以HIF1a和一氧化氮合酶为靶点，在CHF投射到RVLM的细胞中调节PVN神经元的活动。此外，这一假说也得到了验证，即来自肾脏传入终末的投射通过激活HIF1a来调节交感神经兴奋。运动训练对这一轴的调节也将是该项目的一个组成部分。项目III主要研究CHF患者的致敏颈动脉化学反射和颈动脉小体。该项目将确定血流的变化如何转化为KLF2的变化，KLF2是参与化学感受器放电敏感性的关键转录因子。血流影响的下游通路包括NOS、Nrf2和ACE/ACE2将被检测。HIF1a在改变血流的交感-呼吸变化中的作用将被研究。该项目的目标3将评估化学反射介导的肾血流变化如何改变静脉容量和左心功能。最后，每个具体目标 项目III将评估运动训练改变CHF患者化学反射敏感性的作用和机制。所有研究都将使用最先进的技术，范围从分子和遗传到完整动物的综合生理学，无论是否患有CHF。 (摘要结束) Project-001-NRF2：心力衰竭中的神经元氧化应激和SNA(Zucker，Irving H)

 DESCRIPTION (provided by applicant): This Program Project Grant (PPG) renewal describes a series of experiments designed to answer highly relevant questions concerning the mechanisms for sympatho-excitation in chronic heart failure (CHF). There has been a long history of interaction among the PI's in this PPG. We have contributed substantially to the literature in this area and are now proposing new studies that probe deeper into the origins of sympathetic regulation in CHF. Overall, the studies described here provide part of the molecular underpinning of the sympatho-excitatory process in CHF. The studies proposed are highly relevant to the mechanisms of CHF progression in humans. In Project I the focus will be on the role of an important antioxidant transcription factor, namely Nrf2 and its cytosolic teather, Keap1 in the regulation of neuronal oxidative stress in the rostral ventrolateral medulla. More importantly we will demonstrate that Nrf2 competes, within the nucleus, with NFkB for binding to the CREB binding protein thus reducing binding of Nrf2 to antioxidant response elements (AREs). Specific aims of this project will also investigate the role of exercise training and ACE2 in the modulation of Nrf2 in the setting of CHF. Project II will focus on the role of the PVN in sympathetic regulation. The proposed studies target HIF1a and nitric oxide synthase as modulators of PVN neuronal activity in CHF in cells projecting to the RVLM. In addition, the hypothesis is tested that projections from afferent endings in the kidney modulate sympatho-excitation by activation of HIF1a. The modulation of this axis by exercise training will also be a component of this project. Project III concentrates on the sensitized carotid chemoreflex and carotid body in CHF. This project will determine how changes in blood flow translate into alterations in KLF2, a key transcription factor involved in chemoreceptor discharge sensitivity. The downstream pathways in the blood flow effects including NOS, Nrf2 and ACE/ACE2 will be examined. The role of HIF1a on the sympatho-respiratory changes to altered blood flow will be examined. Aim 3 of this project will evaluate how chemoreflex-mediated changes in renal blood flow may alter venous capacitance and left ventricular function. Finally, each of the specific aims of Project III will evaluate the role of and the mechanism by which exercise training alters chemoreflex sensitivity in CHF. All studies will use state-of-the-art techniques ranging from the molecular and genetic to the integrative physiology of intact animals with and without CHF. (End of Abstract) PROJECT-001 - NRF2: NEURONAL OXIDATIVE STRESS AND SNA IN HEART FAILURE (Zucker, Irving H)