Influence of peripheral chemoreceptors and hypoxia on neurovascular regulation and plasticity

在过去的6年里，我在了解缺氧对心血管功能的影响方面取得了重大进展。这包括培训一支热情和成功的HQP团队(n=42)；他们中的大多数人已经过渡到各自领域内的熟练职位。我们共同出版了极具新颖性和影响力的手稿，并在自然科学和工程(NSE)方面取得了技术进步。这笔赠款为未来5年的研究设定了一个令人兴奋的方向。氧气对生命至关重要，缺乏足够的氧气(缺氧)会导致显著的纠正和代偿生理反应。我推测，在缺氧期间，自主神经系统(通过交感和副交感神经系统)是心血管代偿性反应的关键组成部分。我列出了三个相关的研究主题，通过提高我们对自主神经系统与低氧期间心血管反应之间的调节机制的理解，解决了我的假设。主题1将使用直接神经记录(显微神经学)和先进的定制分析软件来定义交感神经元在缺氧期间如何激活和激发。我们将使用生化技术将这种活动与这些神经元释放的神经递质的数量和类型直接联系起来。最后，我们将使用药理激动剂和拮抗剂来量化血管对这种化学信号的反应。主题2将确定副交感神经系统信号在缺氧时对心脏的影响。我们将使用呼吸暂停和药物拮抗剂作为一种强有力的工具来揭示副交感神经系统在缺氧期间的影响。将在清醒和睡眠期间评估在长时间缺氧期间(数小时到数月)对心率和节律的影响的时间进程。主题3由3个研究探险组成，以确定世界高海拔人口的适应表型。这是我们以前在尼泊尔和秘鲁工作的直接延伸。我们将收集第一个关于高海拔埃塞俄比亚人神经心血管控制的数据，他们在海拔最长的地方居住(&gt；7万年)。我们将把这一数据与200年前迁徙到高海拔地区的北美高海拔地区的数据进行对比。这些个体也与我们在北美低地居民的适应工作形成了完美的对比。最后，我们将返回尼泊尔，填补与缺氧期间高海拔和低海拔女性心血管控制相关的巨大空白。所有研究将由HQP领导，HQP将获得重要的技术和理论培训，为他们成为NSE的下一任领导者做好准备。这一系列研究的发现将与生活在高原的2亿人直接相关，也就是数百万人为了工作或娱乐而前往海拔地区，并转化为对呼吸系统或心血管疾病患者的医学研究。

In the last 6 years I have made significant progress towards understanding the influence of hypoxia on cardiovascular function. This includes training a team of enthusiastic and successful HQP (n=42); the majority of whom have transitioned to skilled positions within their fields. Together we have published highly novel and impactful manuscripts, and made technological advances related to Natural Sciences and Engineering (NSE). This grant sets an exciting direction of research for the next 5yrs. Oxygen is critical for life and lack of sufficient oxygen (hypoxia) is met with significant corrective and compensatory physiological responses. I hypothesize that during hypoxia, the autonomic nervous system (via the sympathetic and parasympathetic systems) is a critical component of the compensatory cardiovascular response. I have laid out 3 related themes of research which address my hypothesis by advancing our understanding of the regulatory mechanism linking the autonomic nervous system to cardiovascular responses during hypoxia. Theme 1 will define how sympathetic neurons are activated and fire during hypoxia using direct neural recordings (microneurography) and advanced custom analysis software. We will directly link this activity to the amount and type of neurotransmitters released by these neurons using biochemical techniques. Finally, we will quantify the responsiveness of blood vessels to this chemical signaling using pharmacological agonists and antagonists. Theme 2 will identify the effects of parasympathetic nervous system signaling on the heart during hypoxia. We will use apnea and pharmacological antagonists as a potent tools to unmask the effects of the parasympathetic system during hypoxia. The time-course of influence on cardiac rate and rhythm during prolonged periods of hypoxia (hours to months) will be assessed during wakefulness and sleep. Theme 3 is comprised of 3 research expeditions to define the adaptive phenotypes of the world's high-altitude populations. This is a direct extension of our previous work in Nepal and Peru. We will capture the first data on neuro-cardiovascular control in high-altitude Ethiopians, who have resided at altitude the longest (>70,000yrs). We will contrast this data with high-altitude North American's who migrated to altitude regions only 200yrs ago. These individuals are also the perfect contrast to our acclimatization work in North American Low-landers. Finally, we will return to Nepal to fill a huge gap related to high-lander and low-lander female cardiovascular control during hypoxia. All research will be led by HQP, who will gain significant technical and theoretical training to prepare them as the next leaders in NSE. The findings from this line of research will be directly relevant to the >200million people living at altitude, the millions of people that travel to altitude for work or recreation, and translated to medical research in patients with respiratory or cardiovascular disease.