This renewal proposal is designed to investigate the mechanisms of hyperbaric oxygen induced preconditioning (HBO-PC) in a focal cerebral ischemic model produced by Middle Cerebral Artery Occlusion (MCAO). For broadening of clinical applicability, it was also designed to evaluate efficacy of HBO-PC against other brain injuries by using a global cerebral ischemia model produced by Four Vessel Occlusion (4VO);and a Surgical Brain Injury (SBI) model which represents brain injury caused by neurosurgical procedures. Based on these preliminary results demonstrating HIF-1 specifically responds to HBO, publications by us and others, and the fact that HIF-1 is the main oxygen sensing protein, our Central Hypothesis is that HBO produces preconditioning by transiently inducing HIF-1 and its downstream target genes responsible for cell death and blood-brain barrier (BBB) disruption and thereby leads to ischemic tolerance to subsequent major brain insult. The following specific aims are proposed to address our hypothesis.
Aim 1 : To determine the mechanism of HIF-1 induction by HBO-PC in brain tissue and broad efficacy of HBO-PC. Our specific hypothesis is that HBO-PC produces moderate levels of reactive oxygen species (ROS) which, by destabilization of prolyl hydroxylase 2 (PHD2), induces HIF-1 accumulation in brain tissue. Interventions such as quenching ROS or enhancing PHD2 will abolish induction of HIF-1 by HBO-PC and thereby abolish preconditioning effects. It is expected that HBO-PC is a broadly effective modality that reduces brain injuries as a consequence of MCAO, SBI, and 4VO models.
Aim 2 : To determine the mechanism by which HIF-1 induction leads to tolerance against apoptotic cell death after cerebral ischemia. Our specific hypothesis is that HIF-1, induced by HBO-PC, binds to and stabilizes p53. This p53 accumulation and activation of its downstream proteins: Bax and caspase-3 result in tolerance against subsequent cerebral ischemia-induced cell death. Interventions such as pharmacological inhibition of p53 and caspase-3 are expected to abolish HBO-PC-induced cell protection.
Aim 3 : To determine the mechanism by which HIF-1 induction leads to tolerance against BBB disruption after cerebral ischemia. Our specific hypothesis is that HIF-1, induced by HBO-PC, activates VEGF and its down streams through three possible pathways which will provide tolerance against subsequent cerebral ischemia-induced BBB disruption and brain edema. The long term goal of this proposal is to establish HBO-PC as a clinically means to prevent or reduce brain injuries that can either complicate major cardiac or liver surgeries (4VO model) or that are a result of neurosurgical procedures (MCAO, SBI models). To pursue this goal we will establish the mechanistic basis for HBO-PC at a molecular level. We will also determine the long term beneficial effect of HBO-PC as measured by neurological and neurobehavioral outcomes. The clinical implication of HBO-PC, as an effective, easy to use, and safe modality, could be expanded to multiple brain injuries complicating major surgical procedures.
This project intends to establish mechanisms of brain protection induced by oxygen at elevated pressures for patients with elective surgeries including neurosurgery, cardiac thoracic surgery and liver transplant.
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