Insulin-sensing capabilities of the carotid chemoreceptors

描述(申请人提供)：本申请的目的是确定颈动脉小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F32应用程序提供了极好的智力和强大的实验室培训机会，专注于颈动脉小体调节的综合生理功能。颈动脉化学感受器是一种多模式传感器，以其氧气感应能力而闻名，最近的实验证据表明，它们也可能对胰岛素产生反应。[通过在动物和人类中使用新的平行方法系统地检测颈动脉化学感受器的胰岛素感应能力，拟议的研究将确定颈动脉小体作为影响胰岛素介导的交感兴奋的整合传感器的作用。胰岛素介导的颈动脉化学感受器活性改变可能为高血压、胰岛素抵抗和睡眠呼吸暂停等一系列代谢性疾病的病理生理学提供了潜在的机制。特异性目标1将研究胰岛素对体外激活颈动脉化学感受器的影响。使用分离的大鼠颈动脉小体制剂，我们将直接测量响应胰岛素暴露的颈动脉小体传入活动的变化。我们假设胰岛素会导致颈动脉窦神经活动增加。我们还假设胰岛素将增加对低氧的感觉反应，任何由胰岛素介导的传入神经活动的变化都将随着高氧而减弱。具体目标2将确定颈动脉化学感受器对胰岛素介导的健康人的自主神经和心肺反应的贡献。在目标2a中，我们将比较常氧和高氧条件下肌肉交感神经活性(MSNA)与高胰岛素血症的变化(以抑制颈动脉小体化学感受器介导的反应)。在目标2b中，我们将比较MSNA、通气量和颈动脉小体化学敏感性(低氧呼吸反应，HVR)在对照条件下和低剂量多巴胺(以抑制颈动脉小体化学感受器介导的反应)输注期间与高胰岛素血症的变化。我们假设胰岛素将导致人类MSNA、通气量和化学感受器敏感性的增加。我们还假设，在高氧和/或小剂量多巴胺输注期间，高血糖对MSNA、通气量和HVR的影响将被钝化。]我们提出了新的、高影响力的转译研究，调查颈动脉小体作为影响交感和心肺反射的循环胰岛素的整合感受器的作用。[组建的研究小组，加上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培训环境。重要的是，在体外动物和人体研究中，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影响，这对未来在患者群体中进行定向研究至关重要。]

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.]