Adaptation, plasticity and phylogeny: factors mediating tissue oxygen homeostasis

该计划的长期目标是了解组织如何适应氧气输送和利用的氧气稳态方面的变化。 将使用独特的多模式系统评估组织氧合。它将磁共振成像与近红外（NIR）光谱和植入式间隙传感器（用于氧分压（pO2））相结合。 我们将确定大鼠模型适应慢性缺氧前后组织氧合（定义为血红蛋白饱和度、间质pO2或导致乳酸增加所需的缺氧水平或组织学缺氧标记物的结合）与脑氧代谢率（CMRO2）之间的关系。因此，我们将确定抑制CMRO2的缺氧水平，以及慢性适应如何改变急性反应。我们将确定慢性增加CMRO2（实验性癫痫发作诱导）对组织氧合的影响，如多模式系统所测量的。 我们将使用一种促神经再生的方法来帮助确定大脑氧合适应的能力。在此，我们将比较低地鸟类和斑头雁在不同吸入氧水平范围内的脑pO2。这种动物适合在高海拔和缺氧条件下飞行。我们已经开发出一种独特的pO2传感器，可以长期植入并用于清醒的无限制动物。这将减少与急性组织损伤以及麻醉相关的伪影。这项研究将确定适应是否会导致缺氧期间脑氧水平的正常化，或者对降低水平的耐受性。我们将确定细胞氧传感是否会适应慢性缺氧暴露的模型。缺氧诱导因子（HIF）途径由对细胞内氧敏感的途径调节。 我们将量化适应前后的HIF浓度，并与组织pO2相关，以显示慢性缺氧是否会改变该途径的调节。这项工作将提供关于急性和慢性缺氧如何影响大脑氧合以及大脑适应缺氧的能力的独特信息。

The long term objective of this program is to understand how tissues adapt to changes in oxygen delivery and utilization in terms of the oxygen homeostasis. A unique multimodal system will be used to assess tissue oxygenation. This combines Magnetic Resonance Imaging with near-infrared (NIR) spectroscopy and implantable interstitial sensors (for partial pressure of oxygen (pO2)). We will determine the relationship between tissue oxygenation (defined as either hemoglobin saturation, interstitial pO2, or the level of hypoxia needed to cause increased lactate or the binding of histological hypoxia markers) and cerebral metabolic rate for oxygen (CMRO2) before and after adaptation to chronic hypoxia in the rat model. We will thus identify the level of hypoxia that will inhibit CMRO2 and how the acute response is modified by chronic adaptation. We will determine the effects of chronic increased CMRO2 (induced with experimental seizures) on tissue oxygenation as measured with the multimodal system. We will use a phylogenic approach to help determine the capacity for brain oxygenation to adapt. Here we will compare brain pO2 over a range of inspired oxygen levels in lowland birds with that of the bar-headed goose. This animal is adapted for flight at high altitudes and hypoxic conditions. We have developed a unique pO2 sensor that can be implanted chronically and used in awake unrestrained animals. This will reduce artifacts related to acute tissue damage as well as anesthesia. This study will determine if adaptation results in normalization of brain oxygen levels during hypoxia, or a tolerance to reduced levels. We will determine if cell oxygen sensing will adapt in a model of chronic hypoxia exposure. The hypoxia inducible factor (HIF) pathway is regulated by pathways sensitive to intracellular oxygen. We will quantify HIF concentration before and after adaptation and relate to tissue pO2 to show if regulation of this path is modified by chronic hypoxia. This work will provide unique information on how brain oxygenation is influenced by acute and chronic hypoxia and the capacity of brain to adapt to hypoxia.