Adaptation, plasticity and phylogeny: factors mediating tissue oxygen homeostasis

这项计划的长期目标是了解组织如何根据氧稳态来适应氧输送和利用的变化。一种独特的多模式系统将用于评估组织氧合。它将磁共振成像与近红外(NIR)光谱和植入式间质传感器(用于测量氧分压)结合在一起。我们将确定组织氧合(定义为血红蛋白饱和度、间质pO2，或导致乳酸增加所需的低氧水平或组织学低氧标志物的结合)与大鼠慢性低氧适应前后脑氧代谢率(CMRO2)的关系。因此，我们将确定抑制CMRO2的低氧水平，以及慢性适应如何改变急性反应。我们将确定慢性增加的CMRO2(由实验性癫痫引起)对多模式系统测量的组织氧合的影响。我们将使用系统发生学方法来帮助确定大脑氧合适应的能力。在这里，我们将比较低地鸟和斑头雁在一系列氧气水平上的大脑氧分压。这种动物适合在高海拔和低氧条件下飞行。我们已经开发出一种独特的PO2传感器，可以长期植入，并用于清醒的无拘无束的动物。这将减少与急性组织损伤和麻醉相关的伪影。这项研究将确定适应是否会导致缺氧期间大脑氧气水平的正常化，或者对降低水平的耐受性。我们将确定细胞氧气感应是否会适应慢性低氧暴露的模型。低氧诱导因子(HIF)途径受细胞内氧敏感途径的调控。我们将量化HIF在适应前后的浓度，并与组织PO2相关，以显示慢性缺氧是否改变了这一途径的调节。这项工作将为研究急性和慢性缺氧对大脑氧合的影响以及大脑适应缺氧的能力提供独特的信息。

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.