Role of HIF1-alpha and Renal afferents in Activation of the PVN in Heart Failure

HIF1-α 和肾传入在心力衰竭中 PVN 激活中的作用

基本信息

批准号：
8903575
负责人：
KAUSHIK P PATEL
金额：
$ 35.42万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
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：
2014-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8903575
关键词：
Accounting Address Affect Afferent Neurons Angiotensin II Animal Model Animals Brain Cardiac Output Cardiovascular system Cell Nucleus Chronic Coronary artery Data Denervation Equilibrium Excretory function Exercise Exhibits Gene Transfer Glutamates Goals HIF1A gene Health Heart failure Hypertension Hypothalamic structure Hypoxia Inducible Factor Individual Kidney Lead Ligation Mediating Modality Molecular Morbidity - disease rate N-Methylaspartate NR1 gene Nerve Nervous System Physiology Neuraxis Neurons Neurotransmitters Nitric Oxide Nitric Oxide Synthase Nitric Oxide Synthase Type I Norepinephrine Patients Peripheral Rattus Risk Role Small Interfering RNA Source Techniques Technology Testing Therapeutic Therapeutic Effect Training afferent nerve base cytokine effective therapy gamma-Aminobutyric Acid hypoxia inducible factor 1 interdisciplinary approach mortality paraventricular nucleus relating to nervous system response small hairpin RNA

项目摘要

DESCRIPTION (provided by applicant): Patients with heart failure (HF) and all animal models of HF exhibit an increased sympathetic neural activation, which increases the risk of morbidity and mortality. Standard therapy is to attempt to contain this sympatho- excitation in the face of reduced cardiac output. We have previously observed that neuronal activation within the paraventricular nucleus (PVN) of the hypothalamus may contribute to this elevated neuro-humoral drive. The mechanisms and source of this activation remain to be clearly delineated. Recently we uncovered enhanced excitatory mechanism mediated by 1) an intra-PVN hypoxia-inducible factor (HIF-1�) mechanism: We have found that HIF-1� protein is increased in the PVN of rats with HF; A HIF-1� siRNA administered to the PVN normalizes the increased renal sympathetic nerve activity in rats with HF. 2) A renal nerve dependent mechanism: Renal denervation (RDN) is a new effective therapy for reducing sympathetic outflow in patients with hypertension. Our preliminary data shows that RDN reduces norepinephrine excretion in rats with HF, but not in sham rats, suggesting that RDN reduces sympatho-excitation in HF. Finally, as a therapeutic modality we have shown that exercise training (ExT) reduces activation of HIF-1� in the PVN and decreases neuro- humoral activation in HF. This proposal tests the hypothesis that activation of HIF-1� and/or ascending information from the renal nerves contributes to the increased sympathetic drive in HF. Furthermore, ExT, may normalizes levels of HIF-1� and/or renal afferent input to the PVN in HF. We propose to determine the underlying mechanisms for the activation of HIF-1� and/or ascending information from the renal nerves at the level of the PVN and subsequent sympatho-excitation in rats with HF. This goal will be accomplished by utilizing a multidisciplinary approach, ranging from studies in intact whole animals to studies in brain nuclei to individual neurons. We will use a variety of complementary techniques involving electrophysiological, neuroanatomical, immunohistochemical, molecular, cellular, and lentiviral gene transfer technology. The results will provide significant new information regarding central mechanisms of sympatho-excitation, specifically involvement of HIF-1� and/or ascending information from the renal nerves to the PVN in the increased sympathetic neural activation in the HF state. Understanding the role of these central mechanisms, not studied to date, in the increased sympathetic neural drive will enhance our ability to treat the HF condition and its cardiovascular complications.

描述（由适用提供）：心力衰竭患者（HF）和HF的所有动物模型都暴露了同情神经元激活的增加，这增加了发病率和死亡率的风险。标准疗法是在减少心输出量时试图遏制这种兴奋。我们先前已经观察到，下丘脑的室室核（PVN）内的神经元激活可能有助于这种升高的神经性驱动。这种激活的机制和来源仍有明确描述。最近，我们发现了由1）PVN缺氧诱导因子（HIF-1）机制介导的增强的兴奋机制：我们发现，HF大鼠的PVN增加了HIF-1蛋白；对PVN施用的HIF-1 siRNA使HF大鼠的肾交感神经活动增加。 2）肾神经依赖机制：肾脏神经（RDN）是一种新的有效疗法，可减少高血压患者的交感神经输出。我们的初步数据表明，RDN可以减少HF大鼠的去甲肾上腺素极端，但在假大鼠中却不会议，这表明RDN减少了HF中的交感神经激发。最后，作为一种治疗方式，我们表明运动训练（EXT）降低了PVN中HIF-1的激活，并降低了HF中的神经体液激活。该提案检验了以下假设：HIF-1。和/或肾神经的上升信息的激活有助于HF的交感神经驱动力增加。此外，EXT可以将HF中PVN的HIF-1和肾脏传入输入的水平归一化。我们建议确定在PVN水平上从肾神经中激活HIF-1的基本机制，以及随后在HF大鼠中激活HIF神经的基本机制。该目标将通过利用多学科方法来实现，从完整动物的研究到脑核研究到单个神经元的研究。我们将使用各种涉及电生理，神经解剖学，免疫组织化学，分子，细胞和慢病毒基因转移技术的完整技术。该结果将提供有关HF状态增加的交感神经神经元激活中肾神经到PVN的交感神经，HIF-1和/或上升信息的重要新信息。了解这些中心机制的作用，迄今为止还没有研究，在增加的交感神经元驱动器中，将增强我们治疗HF疾病及其心血管并发症的能力。