Vagal afferent cell bodies as sensors of blood-borne factors

描述（申请人提供）：迷走神经传入神经对血流动力学状态的“一刻到一刻”和“长期”调节起着至关重要的作用。本项目重点研究结节神经节枕动脉微血管的独特性质及其在迷走神经传入活动和心血管功能调节中的重要性。我们的第一个假设是枕动脉微血管系统缺乏有效的“血神经节屏障”，以使循环因子通过与细胞表面受体的相互作用进入结节神经节的迷走神经传入细胞体并调节其活性。这样的系统将允许“时刻到时刻”地调节迷走神经传入的中央定向动作电位，并将传入信息传输到大脑。目前，关于诸如体液诱导的高血压、糖尿病和炎症状态等疾病过程如何影响迷走神经传入神经元中受体的合成和配置，还没有达成共识。我们的第二个假设是枕动脉-结节神经节复合物的独特功能形态允许血源性因子的持续增加，从而改变迷走神经传入细胞体中受体的合成，从而改变这些受体插入细胞体质膜和轴突运输到外周和中枢传入终端的净可用性。这将代表一种新的“长期”内稳态机制，允许迷走神经传入神经有效地适应对传入神经和心血管功能有害的因素水平的增加。我们项目的主要重点是确定枕动脉-结节神经节复合物在对照大鼠和2-肾-1夹（2K-1C）高血压大鼠（一种临床上相关的体液（肾素）依赖性高血压模型）的综合心血管生理中的重要性。我们将采用体内和体外功能技术，以及受体结合/免疫组织化学方法，以全面的方式解决我们的具体目标，即表征(1)血源性因子对迷走神经传入细胞体的可及性，(2)参与关键循环因子对传入细胞体作用的受体亚型，(3)对照和2K-1C高血压大鼠迷走神经传入神经受体表达和功能的时间变化；(4)循环因子调节枕动脉微血管平滑肌张力的受体亚型及其作用。通俗地说，这个项目的目的是确定通过向大脑发送信号来调节血压的神经细胞体是否能够直接对血液中的化学物质做出反应。这种独特的反应机制可能对帮助身体保护心血管系统免受高血压、炎症和糖尿病等威胁人类健康的疾病状态至关重要。

DESCRIPTION (provided by applicant): Vagal afferent nerves play vital roles in the "moment to moment" and "long-term" regulation of hemodynamic status. This project focuses on the unique nature of the occipital artery microvasculature in nodose ganglia and its importance to the regulation of vagal afferent activity and cardiovascular function. Our first hypothesis is that the occipital artery microvasculature lacks an effective "blood-ganglion barrier" in order for circulating factors to gain access to, and regulate the activity of, vagal afferent cell bodies in nodose ganglia via interactions with cell-surface receptors. Such a system would allow for the "moment to moment" regulation of centrally-directed action potentials in vagal afferents and transmission of afferent information into the brain. At present, there is no consensus as to how disease processes such as humorally-induced hypertension, diabetes and inflammatory states affect the synthesis and disposition of receptors in vagal afferent neurons. Our second hypothesis is that the unique functional morphology of the occipital artery-nodose ganglion complex allows sustained increases in blood-borne factors to alter the synthesis of receptors in vagal afferent cell bodies and therefore the net availability of these receptors for insertion into the plasma membranes of the cell bodies and for axonal transport to the peripheral and central afferent terminals. This would represent a novel "long-term" homeostatic mechanism that allows vagal afferents to effectively adapt to increased levels of factors that are detrimental to afferent and cardiovascular function. The major focus of our project is to determine the importance of the occipital artery-nodose ganglion complex in integrative cardiovascular physiology in control rats and in 2-kidney-1 clip (2K-1C) hypertensive rats, a clinically-relevant model of humoral (renin)-dependent hypertension. We will employ functional in vivo, and in vitro techniques, and receptor binding/immunohistochemistry methods in a comprehensive approach to addressing our specific aims, which are to characterize (1) the accessibility of blood-borne factors to vagal afferent cell bodies, (2) the receptor sub-types involved in the actions of key circulating factors on afferent cell bodies, (3) the temporal changes in the expression and function of receptors in vagal afferents of control and 2K-1C hypertensive rats, and (4) the effects of and receptor-subtypes by which circulating factors regulate smooth muscle tone in the occipital artery microvasculature of control and 2K-1C rats. In lay terms, the aim of this project is to determine whether the cell bodies of nerves that regulate blood pressure by sending signals into the brain are able to respond directly to chemicals in the blood. This unique response mechanism may be vital in helping the body to defend the cardiovascular system against disease states that threaten human health such as high blood pressure, inflammation and diabetes.