Adaptation, plasticity and phylogeny: factors mediating tissue oxygen homeostasis

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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.