Mechanisms of Neuroprotection in the Nucleus Tractus Solitarius of Hibernators

冬眠者孤束核的神经保护机制

• 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
• 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' 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

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，被诊断出500,000名患者，每年约30万例。交感神经兴趣在疾病进展中起着重要作用。众所周知，交感神经与疾病预后成反比。正常受试者的运动随着锻炼而增加交感神经活动（SNA），在休息时和运动中响应于HF患者的HF患者增加。这些夸大的SNA反应与HF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HF运动过程中调节自主神经系统的机制。机械和替代敏感的肌肉传入有助于HF中的SNA调节。刺激这些肌肉传入的受体尚未得到精确鉴定和表征。在过去的几年中，我们的研究工作集中在嘌呤能P2X受体，辣椒素受体（TRPV1）和酸感应离子通道中扮演的角色，在引起HF中肌肉收缩异常的SNA反应中所扮演的角色。数据表明，原发性传入神经元中这些受体的异常可能会引发HF中夸张的肌肉反射的发展。尽管我们的实验室和其他人收集了大量证据，显示了这种疾病中肌肉传入介导的反应的交替，但对于原发性传入神经元的基本受体机制知之甚少。前列腺素和腺苷是活性肌肉中重要的副产品，并参与HF中的异常反射反应。该提案的特定目的是研究前列腺素对HF中夸大肌肉反射的贡献。我们假设前列腺素促进了HF大鼠背根神经节（DRG）神经元中P2X受体的反应。该提案的特定目的是确定腺苷对HF中钝的肌肉代谢反射的贡献。我们假设与对照组相比，腺苷在HF中抑制DRG神经元的TRPV1反应。提出的实验基于我们实验室的最近发表的工作以及已收集的试验数据，并将使用全细胞贴剂钳方法在解离的DRG细胞上进行。这些研究的完成将对细胞水平的HF患者的肌肉传入介导的循环反应进行评估。这些研究将为将来的实验奠定基础，以检查新的治疗剂，以治疗这种疾病中的运动不耐受。