Mechanisms of Neuroprotection in the Nucleus Tractus Solitarius of Hibernators

冬眠者孤束核的神经保护机制

基本信息

批准号：
7625397
负责人：
BARBARA Ann HORWITZ
金额：
$ 38.24万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7625397
关键词：
ASIC channel Adenosine Afferent Neurons Animals Attenuated Autonomic nervous system Capsaicin Cells Cessation of life Characteristics Congestive Heart Failure Coronary Data Development Diagnosis Dinoprostone Disease Disease Progression Evaluation Exercise Extracellular Fluid Fluorescence Future Goals Grant Heart failure Hindlimb Laboratories Lead Ligation Literature Little&apos s Disease Mechanoreceptors Mediating Methods Modeling Morbidity - disease rate Muscle Muscle Contraction Myocardial Infarction Nerve Nerve Endings Neurons Nucleus solitarius P2X-receptor Patients Peripheral Play Preparation Prostaglandin Receptor Prostaglandins Publishing Rattus Reflex action Regulation Reporting Research Rest Role Sensory Small Interfering RNA Spinal Ganglia Testing Tracer Vanilloid Work abnormal reflex base capsaicin receptor femoral artery ganglion cell mortality neuronal cell body neuroprotection novel therapeutics outcome forecast patch clamp receptor research study response study characteristics

项目摘要

In the US, congestive heart failure (HF) is a common and lethal disease with 500,000 patients being diagnosed, and with ~300,000 deaths each year. Sympathoexcitation plays a prominent role in disease progression. It is known that sympathoexcitation is inversely related to disease prognosis. Sympathetic nervous activity (SNA) is increased with exercise in normal subjects and is increased in HF patients at rest and in response to exercise. These exaggerated SNA responses are well correlated with morbidity and mortality in HF patients. The long-term goals of the PI are to better understand the mechanisms that regulate the autonomic nervous system during exercise in HF. The mechano- and metabo-sensitive muscle afferents contribute to regulation of SNA in HF. The receptors that stimulate those muscle afferents have yet to be precisely identified and characterized. Over the last several years our research efforts have focused on the roles played by purinergic P2X receptors, capsaicin receptors (TRPV1) and acid sensing ion channels in evoking abnormal SNA responses to muscle contraction in HF. The data indicate that abnormalities in those receptors in primary afferent neurons may initiate the development of an exaggerated muscle reflex in HF. While our laboratory and others have collected substantial evidence showing alternations in muscle afferent-mediated response in this disease, little is known regarding the underlying receptor mechanisms of primary afferent neurons. Prostaglandins and adenosine are important by-products in active muscles and engaged in the abnormal reflex response in HF. Specific Aim #1 of this proposal is to examine contributions of prostaglandin to exaggerated muscle reflex in HF. We hypothesize that prostaglandins facilitate responses of P2X receptors in the dorsal root ganglion (DRG) neurons of HF rats. Specific Aim #2 of this proposal is to determine contributions of adenosine to blunted muscle metaboreflex in HF. We hypothesize that adenosine inhibits TRPV1 responses of DRG neurons to a greater degree in HF as compared with controls. The proposed experiments are based on recently published work from our laboratory as well as pilot data that have been gathered and will be performed on dissociated DRG cells using whole cell patch-clamp methods. Completion of these studies will provide an evaluation of muscle afferent-mediated circulatory responses in HF patients at the cellular level. These studies will lay the groundwork for future experiments to examine novel therapeutics to treat exercise intolerance in this disease.

在美国，充血性心力衰竭 (HF) 是一种常见且致命的疾病，每年诊断出 500,000 名患者，并导致约 300,000 人死亡。交感神经兴奋在疾病进展中发挥着重要作用。已知交感神经兴奋与疾病预后呈负相关。正常受试者的交感神经活动（SNA）随着运动而增加，心力衰竭患者在休息时和运动后也会增加。这些夸大的 SNA 反应与心力衰竭患者的发病率和死亡率密切相关。 PI 的长期目标是更好地了解心力衰竭运动期间调节自主神经系统的机制。机械和代谢敏感的肌肉传入有助于调节 HF 中的 SNA。刺激这些肌肉传入的受体尚未被精确识别和表征。在过去的几年里，我们的研究工作主要集中在嘌呤能 P2X 受体、辣椒素受体 (TRPV1) 和酸感应离子通道在引起心力衰竭肌肉收缩的异常 SNA 反应中所发挥的作用。数据表明，初级传入神经元中这些受体的异常可能会引发心力衰竭时肌肉反射的过度发展。虽然我们的实验室和其他人已经收集了大量证据，表明这种疾病中肌肉传入介导的反应发生了变化，但人们对初级传入神经元的潜在受体机制知之甚少。前列腺素和腺苷是活跃肌肉的重要副产物，参与心力衰竭的异常反射反应。该提案的具体目标#1 是检查前列腺素对心力衰竭中肌肉反射过度的影响。我们假设前列腺素促进 HF 大鼠背根神经节 (DRG) 神经元 P2X 受体的反应。该提案的具体目标#2 是确定腺苷对心力衰竭肌肉代谢反射减弱的影响。我们假设与对照组相比，心衰患者中腺苷更大程度地抑制 DRG 神经元的 TRPV1 反应。拟议的实验基于我们实验室最近发表的工作以及已收集的试点数据，这些数据将使用全细胞膜片钳方法在分离的 DRG 细胞上进行。这些研究的完成将在细胞水平上评估心衰患者肌肉传入介导的循环反应。这些研究将为未来研究治疗这种疾病运动不耐受的新疗法的实验奠定基础。