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气输送和利用的变化，在氧气稳态方面。一个独特的多模式系统将用于评估组织氧合。它结合了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））。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或引起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（cmoro2）之间的关系。因此，我们将确定缺氧水平将抑制cmor2，以及慢性适应如何改变急性反应。我们将通过多模态系统测定慢性cro2升高（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适应的能力。在这里，我们将比较低地鸟类和斑头鹅的脑pO2在吸入氧水平范围内的变化。这种动物适应在高海拔和低氧条件下飞行。我们开发了一种独特的pO2传感器，可以长期植入，并用于清醒的不受约束的动物。这将减少与急性组织损伤和麻醉有关的人工制品。这项研究将确定适应是否会导致缺氧时脑氧水平的正常化，或者对降低水平的耐受性。我们将确定细胞氧传感是否将适应慢性缺氧暴露的模型。缺氧诱导因子（HIF）通路受细胞内氧敏感通路的调控。我们将量化适应前后的HIF浓度，并将其与组织pO2联系起来，以显示慢性缺氧是否改变了这一途径的调节。这项工作将为急性和慢性缺氧如何影响脑氧合以及大脑适应缺氧的能力提供独特的信息。