The overall goal of this R15 AREA proposal is to test whether Antioxidant Response Element (ARE)-mediated gene expression is neuroprotective in Huntington's disease (HD). The are drives the expression of phase II detoxifying/antioxidant enzymes, and as such, may be an effective therapeutic target to attenuate reactive oxygen species (ROS)-induced cell toxicity, which is an underlying element in the development of HD. To this end, we have generated a novel transgenic mouse strain where the are transcription factors Nrf2 and MafK are driven in a tetracycline-inducible manner within forebrain neurons or glia. We will cross these new transgenic mice with a well-established transgenic mouse model of HD (the R6/2 line) to drive cell-type specific expression of Nrf2 and MafK and thereby increase the expression of phase II detoxifying/antioxidant enzymes.
In Aim 1, we will test the neuroprotective effects of ARE-mediated gene expression in the R6/2 mouse model of HD.
In Aim 2, we will perform a systematic analysis of basal and transgenically-induced Nrf2-ARE transcriptional pathway activation in the R6/2 mouse. Overall, the approach we have outlined in this proposal will allow us to discover whether up-regulation of ARE-mediated gene expression is a viable preventative or therapeutic approach for the treatment of HD. Our results should also lead to the identification of new, potentially cytoprotective, targets for future drug design.
Our work is based on the idea that oxidative stress contributes to neuronal damage in Huntington's disease, and our goal is to discover whether it is possible to activate endogenous antioxidant defense systems and achieve protection from neuronal damage. The results of this work will contribute to the future design of neuroprotective therapies for HD.