Regulation of brain oxygenation

点击翻译按钮获取中文摘要

My long term research program aims to determine how oxygen levels in brain are regulated, how the brain adapts to low oxygen (hypoxia) and how hypoxia impacts brain physiology and function. We developed implantable probes to quantify oxygen tension. We showed oxygen declines linearly with inspired oxygen, until a plateau is reached, corresponding to oxygen delivery limitations. We developed a near-infrared (NIRS)/MRI protocol to quantify hypoxia, perfusion and metabolic rate for oxygen (CMRO2) in rodent cortex. We showed that inflammation can cause hypoxia in the brain. As an inflammatory response is ubiquitous in vertebrates, and hypoxia is associated with impaired brain function, there must be a strong adaptive benefit of having hypoxia occur in conjunction with inflammation. This led to the current proposal. We will build on these observations and include technical developments to study the physiological and metabolic changes that occur in brain during inflammation induced hypoxia, and how hypoxia impacts the immune response in brain. In Aim 1 we will develop new NIRS processing that will allow us to extract data on cytochrome oxidase (COO), a mitochondrial enzyme key to using oxygen. We will assess different spectral regions and validate with hypoxia and a mitochondrial inhibitor. The improved capability to assess COO will allow us to quantify mitochondrial redox-a marker of mitochondrial function. In Aim 2 we will characterize the temporal and spatial pattern of inflammation related hypoxia in brain. We will combine NIRS, implanted probes, and histology to study hypoxia induced by inflammation (lipopolysaccharide). In Aim 3 we will test the hypothesis that such inflammation induced hypoxia is associated with mitochondrial impairment, reduced metabolic rate and reduced perfusion. We will quantify arterial saturation, perfusion with 9.4T MRI arterial spin labelling, microvascular hemoglobin saturation with NIRS and CMRO2. COO will be assessed with NIRS, stains for COO and mitochondrial respiration studies. We will quantify hypoxia inducible factor (HIF1-a) and a marker of inflammation (NfkB). We hypothesize that hypoxia can cause a feedback loop to further stimulate inflammation. In Aim 4 we will stimulate inflammation in the presence of acute inspired hypoxia. Animals will be exposed to ½ atmosphere hypobaric hypoxia, and inflammation will be induced by exposure to LPS. We hypothesize that inflammatory markers and physiological responses will be augmented in the presence of hypoxia, supporting the theory of an inflammation-hypoxia cycle. This work will develop non-invasive technology for quantifying brain oxygenation, perfusion, metabolic rate and mitochondrial status in rodents. We will provide new knowledge of the inflammation-hypoxia cycle. As most PhD's do not remain in academia, I include management, communications and entrepreneurship training to ensure my HQP are poised to support Canada's knowledge based economy.