Regulation of brain oxygenation

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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).