We have found recently that the expression of hypoxia-inducible factor-lalpha (HIF-Ialpha) is enhanced in the ischemic tissues after cerebral ischemia; the time course of HIF-Ialpha expression after ischemia is consistent with the time course of apoptosis; hyper/normal baric oxygen (HBO/NBO) suppresses HIF-lalpha, reduces apoptosis, decreases infarct volume, and improves neurological function. These findings have given rise to an overall hypothesis that HBO/NBO is neuroprotective by inhibition of HIF-la and apoptosis. To test this hypothesis, we propose the following four Specific Aims.
The Specific Aim 1 will study the effect of HBO/NBO on brain protection and HIF-lalpha expression. Our specific hypothesis is that HBO/NBO improves brain morphology and function after cerebral ischemia and decreases HIF-lalpha expression.
The specific Aim 2 will study the mechanism of HBO/NBO on HIF-la degradation. Our specific hypothesis is that HBO/NBO increases tissue oxygen and promotes the degradation of HIF-lalpha, especially the complex of HIF-Ialpha with p53. HBO/NBO modulates other HIF-lalpha regulating factors including proteasomal activity and insulin-like growth factor-l.
The Specific Aim 3 will study the effect of HBO/NBO on HIF-lalpha target genes involved in apoptosis including P53, proapoptotic proteins Nip3, and caspase-9. Our specific hypothesis is that HIF-Ialpha activates apoptotic genes; HBO/NBO reduces HIF-lalpha target apoptotic genes and reduces apoptosis.
The Specific Aim 4 will study the effect of HBO/NBO on HIF-la target genes involved in brain metabolism including glycolytic enzymes, glucose transporters, and inducible nitric oxide synthase (iNOS). Our specific hypothesis is that HBO/NBO reduces glucose, pyruvate, lactate, and nitric oxide (NO) in the ischemic regions by regulating the expression of glycolytic enzymes, glucose transporters and reducing iNOS. We will use a middle cerebral artery occlusion and reperfusion (MCAO/R) rat model in all studies, and we plan to use only one transient (1 hr) HBO/NBO treatment at 3 hrs after reperfusion to avoid the possible harmful effect associated with prolonged HBO/NBO therapy, which might enhance lipid peroxidation. The long-term goal of this study is to establish a role of HBO/NBO as a treatment in acute stroke and to identify the molecular mechanisms of its brain protection.
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