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。该项目提供了一个优秀的智力和强大的实验室培训的机会，F32的应用集中在综合生理功能的调节颈动脉体。颈动脉化学感受器是多模态传感器，以其氧传感能力而闻名，最近的实验证据表明它们也可能对胰岛素产生反应。[By在动物和人类中使用新的平行方法系统地检查颈动脉化学感受器的胰岛素感应能力，所提出的研究将确定颈动脉体作为影响胰岛素介导的交感兴奋的集成传感器的作用。胰岛素介导的颈动脉化学感受器活性的变化可能为一系列代谢性疾病（包括高血压、胰岛素抵抗和睡眠呼吸暂停）的病理生理学提供潜在机制。具体目标1将检查胰岛素对离体颈动脉化学感受器激活的影响。使用离体大鼠颈动脉体制备，我们将直接测量响应胰岛素暴露的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被高氧钝化。具体目标2将确定健康人颈动脉化学感受器对胰岛素介导的自主神经和心肺反应的贡献。在目标2a中，我们将比较在常氧和高氧条件下高胰岛素血症的肌肉交感神经活动（MSNA）的变化（以抑制颈动脉体化学受体介导的反应）。在目标2b中，我们将比较在对照条件下和低剂量多巴胺输注（以抑制颈动脉体化学受体介导的反应）期间MSNA、通气和颈动脉体化学敏感性（缺氧性缓解反应，HVR）与高胰岛素血症的变化。我们假设胰岛素会导致MSNA、通气和化学感受器敏感性增加。我们还假设高胰岛素血症对MSNA、通气和HVR的影响在高氧和/或低剂量多巴胺输注期间将减弱。我们提出了新的，高影响力，和翻译研究颈动脉体的作用，作为综合传感器的循环胰岛素的影响交感神经和心肺反射。[The研究团队的集合，结合马约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培训环境。重要的是，在离体动物和人体研究中，将在严格控制的条件下收集基本生理数据，以系统地检查循环胰岛素水平的急性效应，这对于患者群体中的未来靶向研究至关重要。

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.]