NF-E2 related factor (Nrf2) driven transcription of the antioxidant response element (ARE) genes is one the main protective mechanisms to counteract oxidative insult. Several studies have shown that Nrf2 can protect the blood brain barrier (BBB) in event of cerebral ischemia-reperfusion (IR). However whether Nrf2 still continues to be beneficial to chronic smokers subjected to a life-long oxidative stress has never been addressed. In our earlier published studies, we have shown that the extent of BBB injury following TS exposure is directly dependent on the oxidative potential of the tobacco product where antioxidant supplementation is protective and reduces TS toxicity. Preliminary studies from our lab also indicate that oxidative stress arising from acute TS exposure does lead to activation of the Nrf2-ARE pathway. What we postulate however is that the Nrf2-ARE pathway in circumstances of chronic TS exposure may be compromised thus possibly impairing its protective functions at the level of the BBB. This may leave the BBB excessively vulnerable to other harmful stimuli such as ischemic injuries. In this scenario, our underlying hypothesis is that that Nrf2 driven activation of ARE pathway may be compromised in a BBB chronically exposed to tobacco smoke (TS); which in an event of cerebrovascular ischemic injury may lead to exacerbated loss of BBB integrity/function and secondary brain injury. In addition, we will be extending these studies to test the therapeutic potential of drugs enhancing Nrf2 activity to counteract the harmful effects of TS in an ischemic setting. Both in vitro (including static cell culture and novel flow-based dynamic in vitro -DIV-BBB models) as well as in vivo (transient middle cerebral artery occlusion tMCAO-models following chronic TS exposure) approaches will be utilized to assess the Nrf2 pathway and extent of BBB injury. The main goals we aim to study this proposal include: Specific Aim 1: To investigate the functional / pathological response of Nrf2 and its downstream signaling at the BBB following ischemia-reperfusion injury post chronic TS exposure.Specific Aim 2: To evaluate the therapeutic effectiveness of Nrf2 enhancers in protecting the BBB from IR injury following chronic TS exposure.
|Program type||Predoctoral Fellowship|
|Effective start/end date||01/01/2015 → 05/10/2015|