Subarachnoid hemorrhage (SAH) is a devastating disease carrying with it a mortality of 50% within the first 30 days (30% of patients die from the impact of the initial bleeding, 10% die from re-bleeding and 10% die from delayed cerebral vasospasm). Therefore, most patients die from early brain injury after the impact of bleeding. One of the most important but un-addressed issues in SAH is the early brain neurovascular injury especially cerebral endothelial apoptosis. Endothelial apoptosis initiates blood-brain barrier (BBB) disruption leading to brain edema, which expands brain volume to increase intracranial pressure, thus decreasing cerebral blood flow, impairing cerebral perfusion and oxygenation, and causing additional ischemic brain injury. Our preliminary data from an established rat filament perforate SAH model demonstrates that apoptosis occurs in endothelial cells within 24 hours and in neural cells at 24-72 hours after SAH. This time course provides a window of opportunity for clinical intervention, if basic research can identify promising therapeutic targets. Our overall hypothesis is SAH produces apoptosis in cerebral endothelial cells by activation of distinct death pathways and prevention of apoptosis in cerebral endothelial cells will reduce brain injury.
In Specific Aim 1, we will examine the hypothesis that cerebral endothelial apoptosis enhances early brain injury which is responsible for the high mortality and morbidity after SAH;therefore, the time course of apoptosis opens a window of opportunity for clinical intervention.
In Specific Aim 2, we will examine the hypothesis that mitochondrial apoptotic pathways, especially p53- and apoptosome (Apaf-1-cytochrome C-caspase-9)- dependent pathways, are involved in endothelial apoptosis and inhibition of p53 protects BBB integrity and reduce early brain injury.
In Specific Aim 3, we will examine the hypothesis that receptor apoptotic pathways, especially TNFalpha, TNFR-1, FADD, and caspase-8, contribute to endothelial apoptosis and neurovascular protection will prevent early brain injury. The established filament perforate rat SAH model will continue to be used in these preclinical studies. We expect that our results will ultimately identify potential therapeutic targets of the apoptosis pathway for the clinical treatment of early brain injury after SAH.
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