Regulation of brain oxygenation

大脑对氧气有绝对的需求，然而许多物种即使在低氧（缺氧）的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，并将其应用于研究缺氧时的大脑功能。增加耐受性的机制包括“缺氧反应”，短期转变为厌氧能量产生，更长期的适应包括新血管的生长。许多中长期反应是由缺氧诱导因子（HIF-1a）调节的，HIF-1a通过脯氨酸羟化酶（PHD）途径受氧调节。我最近发现炎症会导致缺氧。研究还表明，在刺激缺氧反应的同一途径上，PHD也刺激了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。对这种相互作用几乎一无所知，这意味着缺氧反应调节只了解了一半，需要在炎症存在的情况下重新研究。我将建立一个小动物成像系统，使用高场（9.4T） MRI和近红外光谱（NIRS）来测量区域脑氧摄取（cro2）和线粒体氧化。我发明了植入式氧气传感器。氧合是一个敏感的标志物之间的平衡交付和cro2。我将结合我独特的技术，量化氧输送路径中的多个点（动脉、毛细血管、组织和细胞内氧合），测量急性和慢性缺氧时的脑氧合和血流量。这样我就可以用数学模型来模拟氧气的输送。然后我就能确定炎症调节输送和cro2的位置。我将使用两种小鼠炎症模型来确定炎症是否刺激缺氧并在缺氧时抑制cro2。我将与世界上研究北极地鼠缺氧耐受性的专家合作，量化炎症对缺氧耐受性物种脑氧合和缺氧反应的影响。我预测炎症对耐缺氧物种的影响较小，因为炎症刺激会抑制这种反应，使动物更容易受到伤害。这项工作将为定量脑氧输送提供新技术。我将提供关于大脑如何对缺氧做出反应以及HIF和NfkB分子途径（缺氧和炎症反应）之间相互作用的新基础知识。

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).