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: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=717570
• 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 redoxa 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-) 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（缺氧）以及缺氧如何影响大脑生理和功能。 我们开发了植入式探针来量化氧张力。我们发现氧气随着吸入氧气线性下降，直到达到一个平台，对应于氧气输送限制。我们开发了一种近红外（NIRS）/MRI协议，以量化缺氧，灌注和代谢率为氧（CMRO 2）在啮齿动物皮层。我们发现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，并且缺氧与脑功能受损相关，因此缺氧与炎症一起发生一定具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，包括技术发展，以研究炎症诱导缺氧期间大脑中发生的生理和代谢变化，以及缺氧如何影响大脑中的免疫反应。 在目标1中，我们将开发新的近红外光谱处理，使我们能够提取细胞色素氧化酶（COO）的数据，这是一种利用氧气的线粒体酶。我们将评估不同的光谱区域，并使用缺氧和线粒体抑制剂进行验证。评估COO的改进能力将使我们能够量化线粒体功能的线粒体氧化还原标记物。在目标2中，我们将描述脑中炎症相关缺氧的时间和空间模式。我们将结合联合收割机、植入探针和组织学来研究炎症（脂多糖）诱导的缺氧。在目标3中，我们将检验这样的炎症诱导的缺氧与线粒体损伤、代谢率降低和灌注减少相关的假设。我们将用9.4T MRI动脉自旋标记定量动脉饱和度、灌注，用NIRS和CMRO 2定量微血管血红蛋白饱和度。将使用NIRS、COO染色和线粒体呼吸研究评估COO。我们将定量缺氧诱导因子（HIF 1-）和炎症标志物（NfkB）。我们假设缺氧可以引起反馈回路，进一步刺激炎症。在目标4中，我们将在急性吸入性缺氧的存在下刺激炎症。将动物暴露于1/2大气压低压缺氧，并且通过暴露于LPS诱导炎症。我们假设炎症标志物和生理反应将在缺氧的存在下增强，支持炎症-缺氧循环的理论。 这项工作将开发用于定量啮齿动物脑氧合，灌注，代谢率和线粒体状态的非侵入性技术。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，我包括管理，通信和创业培训，以确保我的HQP准备支持加拿大的知识经济。