Following traumatic brain injury (TBI) there is copious release of oxygen radicals that damage proteins, DNA and cell membranes ultimately resulting in long-term neurological disabilities. Our laboratory has shown that K+ channels, which are key to neuronal excitability and survival, are substrates of free radicals. In particular, we showed tht oxidation of KCNB1 (formerly Kv2.1), a K+ channel abundant in brain, induces neuronal death by apoptosis via a Src tyrosine kinase mediated pathway. We have identified a FDA-approved, blood-brain barrier permeable drug that directly impinges on this apoptotic pathway. KCNB1 plays a major role in determining the intrinsic excitability of neurons of the cortex and hippocampus. This implies that-following traumatic injury-oxidized KCNB1 channels and/or the other components of the signaling pathways activated by their oxidation may contribute to loss of brain function. The broad goal of this project is to address the role of oxidation of KCNB1channels in traumatic brain injury in vivo and in vitro. We will evaluate the mechanism by which oxidized KCNB1 channels contribute to neuronal death, their potential contribution to the tissue damage that occurs following traumatic brain injury and the therapeutic potential of a FDA-approved drug. Experimental testing will be carried out in mice, including a transgenic mouse expressing a KCNB1 variant resistant to oxidation and cultured primary neurons. As no effective pharmacological treatment exists for traumatic brain injury, our proposal to test the role of oxidation of KCNB1 represents a critical step forward in determining whether KCNB1 and other components of the signaling pathways activated by its oxidation, such as Src tyrosine kinases, represent bona fide drug targets for limiting the cellular devastation that accompanies traumatic brain injury. In addition, this research will add important insight into both the regulation and th downstream pathways impacted by the channel.
|Effective start/end date||4/1/16 → 3/31/18|
- National Institutes of Health (NIH)