Regulation of brain oxygenation

脑氧合作用的调节

• 批准号: RGPIN-2015-06517
• 负责人: Dunn, Jeff
• 金额: $ 2.4万
• 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: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=591108
• 关键词: Regulation; brain; oxygenation

The brain has an absolute requirement for oxygen and yet many species maintain brain function even under conditions of low oxygen (hypoxia). My long term program is to develop technologies to measure oxygenation and apply them to study brain function during hypoxia. Mechanisms that increase tolerance involve a “hypoxia response” with short term shifts to anaerobic energy production and more long term acclimation that includes growth of new blood vessels. Much of the medium to long term response is regulated by hypoxia inducible factor (HIF-1a) which is regulated by oxygen through the prolyl-hydroxylase (PHD) path. I recently showed inflammation causes hypoxia. It has also been shown that the same path which stimulates hypoxia response, PHD also stimulates the master molecular regulator of inflammation--NfkB. This proves that inflammation and hypoxia responses are interdependent. Almost nothing is known about this interaction which means that hypoxia response regulation is only half understood and needs to be re-investigated in the presence of inflammation. I will build a small animal imaging system using high field (9.4T) MRI and near-infrared spectroscopy (NIRS) to measure regional cerebral oxygen uptake (CMRO2) and mitochondrial oxidation. I developed implantable oxygen sensors. Oxygenation is a sensitive marker of the balance between delivery and CMRO2. I will combine my unique technologies to quantify multiple points in the oxygen delivery path (arterial, capillary, tissue and intracellular oxygenation) to measure brain oxygenation and blood flow during acute and chronic hypoxia. This will allow me to mathematically model oxygen delivery. I can then identify where inflammation modulates delivery and CMRO2. I will use two mouse models of inflammation to determine if inflammation stimulates hypoxia and inhibits CMRO2 during hypoxia. I will collaborate with the world’s expert on hypoxia tolerance in the arctic ground squirrel to quantify the impact of inflammation on both brain oxygenation and the hypoxia response in a hypoxia tolerant species. I predict that inflammation will have less impact in a hypoxia tolerant species since stimulation of inflammation could inhibit this response and make the animal more vulnerable. This work will develop new technology for quantifying oxygen delivery in brain. I will provide new fundamental knowledge about how brain responds to hypoxia and the interplay between the HIF and NfkB molecular pathways (hypoxia and inflammation responses).

大脑对氧气有绝对的需求，但许多物种即使在低氧（缺氧）条件下也能维持大脑功能。我的长期计划是开发测量氧合的技术，并应用它们来研究缺氧期间的大脑功能。涉及“缺氧反应”，短期转变为无氧能量产生和更长期的适应，包括新血管的生长，大部分中长期反应是由缺氧诱导因子调节的。 （HIF-1a）通过脯氨酰羟化酶（PHD）途径受氧调节，最近表明炎症会导致缺氧。还表明，PHD 刺激缺氧反应的同一途径也会刺激炎症的主要分子调节剂。 --NfkB。这证明炎症和缺氧反应是相互依赖的，这意味着缺氧反应调节只有一半的了解，需要在存在的情况下重新研究。我将使用高场 (9.4T) MRI 和近红外光谱 (NIRS) 构建小动物成像系统来测量局部脑摄氧量 (CMRO2) 和线粒体氧化。我开发了植入式氧合传感器。我将结合我独特的技术来量化氧气输送路径（动脉、毛细血管、组织和细胞内氧合）中的多个点，以测量脑氧合和血液。这将使我能够对氧气输送进行数学建模，然后我将使用两种炎症小鼠模型来确定炎症是否会刺激缺氧并抑制缺氧期间的 CMRO2。与世界专家合作研究北极地松鼠的缺氧耐受性，以量化炎症对耐缺氧物种的大脑氧合和缺氧反应的影响，我预测炎症将会发生。对耐缺氧物种的影响较小，因为炎症刺激可能会抑制这种反应并使动物更加脆弱。这项工作将开发量化大脑中氧气输送的新技术，我将提供有关大脑如何响应缺氧和缺氧的新基础知识。 HIF 和 NfkB 分子途径（缺氧和炎症反应）之间的相互作用。