Adaptation, plasticity and phylogeny: factors mediating tissue oxygen homeostasis

适应、可塑性和系统发育：介导组织氧稳态的因素

• 批准号: 386056-2010
• 负责人: Dunn, Jeff
• 金额: $ 2.55万
• 依托单位: University of Calgary
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2013
• 资助国家: 加拿大
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=528728
• 关键词: Adaptation; plasticity; phylogeny; factors; mediating

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.

该计划的长期目标是了解组织如何适应氧输送和氧稳态利用的变化。 将使用独特的多模式系统来评估组织氧合。它结合了磁共振成像、近红外 (NIR) 光谱和植入式间隙传感器（用于测量氧分压 (pO2)）。 我们将确定适应前后的组织氧合（定义为血红蛋白饱和度、间质 pO2 或导致乳酸增加或组织学缺氧标志物结合所需的缺氧水平）与脑氧代谢率 (CMRO2) 之间的关系大鼠模型慢性缺氧。因此，我们将确定抑制 CMRO2 的缺氧水平以及如何通过慢性适应来改变急性反应。我们将通过多模式系统测量确定慢性增加的 CMRO2（由实验性癫痫发作引起）对组织氧合的影响。 我们将使用系统发育方法来帮助确定大脑氧合的适应能力。在这里，我们将比较低地鸟类和斑头雁在一系列吸入氧水平下的大脑 pO2。这种动物适合在高海拔和缺氧条件下飞行。我们开发了一种独特的 pO2 传感器，可以长期植入并用于清醒、不受约束的动物。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正常化，或对降低水平的耐受性。我们将确定细胞氧传感是否适用于慢性缺氧暴露模型。缺氧诱导因子（HIF）途径受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，并将其与组织 pO2 相关联，以显示该路径的调节是否因慢性缺氧而改变。这项工作将提供有关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。