Regulation of brain oxygenation

脑氧合作用的调节

• 批准号: RGPIN-2020-05225
• 负责人: Dunn, Jeffrey
• 金额: $ 2.91万
• 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: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=764450
• 关键词: Regulation; brain; oxygenation

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.

我的长期研究计划旨在确定大脑中的氧气水平是如何调节的，大脑如何适应低氧(低氧)，以及低氧如何影响大脑的生理和功能。我们开发了可植入的探头来量化氧分压。我们发现氧气随着吸入氧气的增加呈线性下降，直到达到一个与氧气输送极限相对应的平台。我们开发了一种近红外(NIRS)/MRI方法来量化啮齿动物皮质的缺氧、灌流和氧代谢率(CMRO2)。我们的研究表明，炎症会导致大脑缺氧。由于炎症反应在脊椎动物中普遍存在，而低氧与大脑功能受损有关，因此低氧与炎症同时发生肯定有很强的适应性益处。这导致了目前的提议。我们将在这些观察的基础上，包括技术进展，研究炎症诱导的低氧过程中脑内发生的生理和代谢变化，以及低氧如何影响脑内的免疫反应。在目标1中，我们将开发新的近红外光谱技术，使我们能够提取细胞色素氧化酶(COO)的数据，COO是利用氧气的关键线粒体酶。我们将评估不同的光谱区域，并用缺氧和线粒体抑制剂进行验证。评估COO能力的提高将使我们能够量化线粒体氧化还原--线粒体功能的标志。在目标2中，我们将描述炎症相关的脑内缺氧的时间和空间模式。我们将结合近红外光谱、植入的探针和组织学来研究炎症(脂多糖)引起的缺氧。在目标3中，我们将检验这样一个假设，即这种炎症导致的低氧与线粒体损伤、代谢率降低和血流灌注减少有关。我们将用9.4T磁共振动脉自旋标记定量动脉血饱和度、血流灌注，用NIRS和CMRO2测定微血管血红蛋白饱和度。COO将通过近红外光谱、COO染色和线粒体呼吸研究进行评估。我们将对缺氧诱导因子(HIF1-a)和炎症标志物(NFkB)进行量化。我们假设缺氧可以引起一个反馈回路，进一步刺激炎症。在目标4中，我们将在急性缺氧的情况下刺激炎症。动物将暴露在1/2的常压低氧环境中，并通过暴露于脂多糖诱导炎症。我们假设炎症标记物和生理反应在低氧条件下会增强，支持炎症-低氧循环的理论。这项工作将开发非侵入性技术来量化啮齿类动物的脑氧合、脑血流、代谢率和线粒体状态。我们将提供炎症-缺氧循环的新知识。由于大多数博士不会留在学术界，我将管理、沟通和创业培训包括在内，以确保我的HQP准备好支持加拿大的知识经济。