Insulin-sensing capabilities of the carotid chemoreceptors

描述（由申请人提供）：本申请的目的是确定颈动脉体化学感受器是否参与胰岛素介导的交感神经兴奋。该项目为专注于颈动脉体调节的综合生理功能的F32应用提供了极好的智力和强大的实验室培训机会。颈动脉化学感受器是一种多模态传感器，以其氧感应能力而闻名，最近的实验证据表明它们也可能对胰岛素有反应。[通过在动物和人类中使用新颖的、平行的方法系统地检查颈动脉化学感受器的胰岛素感知能力，拟议的研究将确定颈动脉体作为影响胰岛素介导的交感神经兴奋的综合感受器的作用。]胰岛素介导的颈动脉化学受体活性变化可能为高血压、胰岛素抵抗和睡眠呼吸暂停等一系列代谢紊乱的病理生理学提供潜在机制。特异性目的1将研究胰岛素对颈动脉化学受体激活的体外影响。使用离体大鼠颈动脉体制备，我们将直接测量胰岛素暴露后颈动脉体传入活动的变化。我们假设胰岛素会导致颈动脉窦神经活动增加。我们还假设胰岛素会增加对缺氧的感觉反应，并且任何胰岛素介导的传入神经活动的变化都会因高氧而减弱。特异性目的2将确定颈动脉化学感受器对健康人类胰岛素介导的自主神经和心肺反应的贡献。在Aim 2a中，我们将比较常氧和高氧条件下高胰岛素血症患者肌肉交感神经活动（MSNA）的变化（以抑制颈动脉体化学受体介导的反应）。在Aim 2b中，我们将比较控制条件下和低剂量多巴胺输注（抑制颈动脉体化学受体介导的反应）期间高胰岛素血症患者的MSNA、通气和颈动脉体化学敏感性（低氧通气反应，HVR）的变化。我们假设胰岛素会导致人的MSNA、通气和化学受体敏感性的增加。我们还假设高胰岛素对MSNA、通气和HVR的影响在高氧和/或低剂量多巴胺输注期间会减弱。我们提出新颖的、高影响的和转化性的研究，研究颈动脉体作为循环胰岛素的综合传感器的作用，影响交感神经和心肺反射。[研究团队集结，结合梅奥诊所和芝加哥大学的广泛资源，为完成这一领域的研究提供了最佳的训练环境。重要的是，基本的生理数据将在严格控制的条件下，在离体动物和人类研究中收集，以系统地检查循环胰岛素水平的急性效应，这对未来在患者群体中的靶向研究至关重要。

DESCRIPTION (provided by applicant): The goal of this application is to determine if the carotid body chemoreceptors are involved in insulin-mediated sympathoexcitation. This project provides an excellent intellectual and a robust laboratory training opportunity for an F32 application focusing on integrative physiological functions regulated by the carotid bodies. The carotid chemoreceptors are polymodal sensors known for their oxygen-sensing capabilities and recent experimental evidence suggests they may also respond to insulin. [By systematically examining insulin-sensing capabilities of the carotid chemoreceptors using novel, parallel approaches in both animals and humans, the proposed studies will determine the role of the carotid bodies as integrated sensors influencing insulin-mediated sympathoexcitation. Insulin-mediated changes in carotid chemoreceptor activity may provide a potential mechanism for the pathophysiology of a series of metabolic disorders including hypertension, insulin resistance, and sleep apnea. Specific Aim 1 will examine the effect of insulin on carotid chemoreceptor activation ex vivo. Using an isolated rat carotid body preparation, we will directly measure changes in carotid body afferent activity in response to insulin exposure. We hypothesize insulin will result in an increase in carotid sinus nerve activity. We also hypothesize insulin will increae the sensory response to hypoxia, and any insulin-mediated changes in afferent nerve activity will be blunted with hyperoxia. Specific Aim 2 will determine the contribution of the carotid chemoreceptors to insulin-mediated autonomic and cardiorespiratory responses in healthy humans. In Aim 2a, we will compare changes in muscle sympathetic nerve activity (MSNA) with hyperinsulinemia under normoxic and hyperoxic conditions (to inhibit carotid body chemoreceptor- mediated responses). In Aim 2b, we will compare changes in MSNA, ventilation, and carotid body chemosensitivity (hypoxic ventilatory response, HVR) with hyperinsulinemia under control conditions and during a low-dose infusion of dopamine (to inhibit carotid body chemoreceptor-mediated responses). We hypothesize insulin will result in an increase in MSNA, ventilation, and chemoreceptor sensitivity in humans. We also hypothesize the effect of hyperinsuilnemia on MSNA, ventilation, and HVR will be blunted during hyperoxia and/or low-dose dopamine infusion.] We propose novel, high impact, and translational studies investigating the role of the carotid bodies as integrated sensors of circulating insulin that influence sympathetic and cardiorespiratory reflexes. [The research team assembled, combined with the extensive resources at the Mayo Clinic and University of Chicago, provides the optimal training environment to complete studies in this area. Importantly, basic physiological data will be collected under tightly controlled conditions in both ex vivo animal and human studies to systematically examine acute effects of circulating insulin levels that are critical for future targeted studies in patient populations.]