Influence of peripheral chemoreceptors and hypoxia on neurovascular regulation and plasticity

点击翻译按钮获取中文摘要

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.