Neuro-Circulatory Function in Chronic Heart Failure

慢性心力衰竭的神经循环功能

• 批准号: 8078630
• 负责人: Irving H Zucker
• 金额: $ 7.57万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-05 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8078630
• 关键词: Address; Agonist; Aldosterone; Animals; Antioxidants; Area; Blood flow; Carotid Body; Chemoreceptors; Chronic; Conscious; Enzymes; Exercise; Face; G Protein-Coupled Receptor Genes; Generations; Genetic Transcription; Glomus Cell; Glutamates; Goals; Heart failure; Hypoxia; Intervention; Literature; Measurement; Mediating; Mediator of activation protein; Nerve; Neuraxis; Participant; Pathogenesis; Pathway interactions; Patients; Play; Potassium Channel; Process; Program Research Project Grants; Property; Proteins; Recording of previous events; Reflex action; Regulation; Research; Research Personnel; Role; Series; Signaling Molecule; Skeletal Muscle; Sum; System; Technology; Training; Transcriptional Regulation; Translations; Work; clinically relevant; design; experience; noradrenergic; novel; receptor; research study; response; shear stress; transcription factor

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, we believe that sympathetic activation is mediated by a combination of increased sympatho-excitatory reflexes, blunted sympatho-inhibitory reflexes and changes in signaling molecules in the central nervous system and in the periphery. Four projects are proposed. In Project I the focus will be on the mechanism by which the ATiR is upregulated in the RVLM of animals with heart failure. This unique property of a GPCR to be upregulated in the face of increased agonist (Ang II) suggests a pivotal role for this receptor in the pathogenesis of sympatho-excitation in CHF. We will determine alterations in transcriptional regulation of the ATiR and the roles of ACE, ACE2, ROS and exercise training. Project II will focus on the role of the PVN in sympathetic regulation. Building on studies showing abnormalities in the GABA-glutamate systems in the PVN, this project now proposes that an ascending noradrenergic pathway modulated, in part, by aldosterone plays an important role in sympatho-excitation in CHF. The interactions between aldosterone and nNOS will be examined in this project. Finally, the role of exercise training on nNOS and aldosterone in CHF will be investigated. Project III concentrates on the sensitized carotid chemoreflex in CHF. This project has clearly shown chemoreceptor and chemoreflex sensitization in CHF and an important role for K* channel modulation in glomus cells by Ang II and NO in response to hypoxia. This project now focuses on the role of altered carotid body blood flow as a mediator of chemoreflex sensitivity. These studies will investigate the role of a novel transcription factor, KLF2, in mediating transduction between endothelial shear stress and mediators of K* channel function. The role of Ang (1-7) will also be investigated in this project. Project IV will investigate the role of skeletal muscle reflexes on sympatho-excitation in CHF. Specifically, this project will determine if ROS play an important role in altering the sensitivity of both chemically sensitive group III afferents and mechanically sensitive group IV afferents. The role of exercise training in modulating ROS generation and antioxidant enzymes in animals with CHF will also be investigated in this project.

该计划项目赠款（PPG）续订描述了一系列实验，旨在回答有关慢性心力衰竭（CHF）的交感神经激发机制的高度相关问题。在PPG中，PI之间存在悠久的相互作用历史。我们为该领域的文献做出了基本贡献，现在提出了新的研究，以更深入地探讨CHF中交感神经调节的起源。总体而言，我们认为交感神经激活是由增加的交感神经反射，钝性的交感神经抑制反射和信号分子中中枢神经系统和周围的信号分子变化的组合所介导的。提出了四个项目。在项目I中，重点将放在心力衰竭的动物RVLM中ATIR上调的机制。面对增加的激动剂（ANG II），GPCR的这种独特的特性表明该受体在CHF的交感神经发病机理中起关键作用。我们将确定AT​​IR的转录调节的改变以及ACE，ACE2，ROS和运动训练的作用。项目II将重点介绍PVN在交感调节中的作用。基于研究表明PVN中GABA - 谷氨酸系统异常的研究，该项目现在提出，升高的去甲肾上腺素能途径在某种程度上由醛固酮调节，部分地在CHF的交感神经激发中起着重要作用。该项目将检查醛固酮和NNO之间的相互作用。最后，将研究对CHF的NNO和醛固酮的运动训练的作用。项目III集中在CHF中的敏化颈动脉化学反射上。该项目清楚地表明了CHF中的化学感受器和化学反射敏化，以及ANG II的glomus细胞中K*通道调节的重要作用，而没有响应缺氧的NO。现在，该项目着重于改变颈动脉体血流作为化学反射灵敏度的介体的作用。这些研究将研究一种新型转录因子KLF2在介导内皮剪切应力和K*通道功能介质之间的转导中的作用。 ANG（1-7）的作用也将在该项目中进行研究。 IV项目将研究骨骼肌反射在CHF中的交感神经兴奋中的作用。具体而言，该项目将确定ROS是否在改变化学敏感的III组传入和机械敏感的IV组传入方面是否起重要作用。在该项目中，还将研究运动训练在具有CHF动物中的ROS产生和抗氧化酶中的作用。