Naseem Ansari , Ph.D., Professor
The research in my laboratory involves the investigations to understand the biochemical mechanism(s) of oxidative pathologies such as senile cataract, Age-Related Macular Degeneration and secondary complications of diabetes. Our reseach has shown that lipid peroxidation end products are the toxic mediators in the above-mentioned oxidative pathologies. We have focused on 4-hydroxynonenal (HNE) and 4-hydroxyhexenal (HHE), the most toxic lipid peroxidation end products. The presence of an α - Β unsaturated double bond and aldehyde group impart reactivity to these lipid derived aldehydes, due to which they readily conjugate the protein having a reactive cysteine, histidine or epsilon amino group. We have established that there is increased formation of membrane protein-HNE adducts under oxidative stress which causes membrane fluidity changes leading to alteration in calcium homeostasis, activation of caspases and cell death. Cytoskeletal proteins such as actin, vimentin and tubulin, and gap junction proteins such as connexins are specifically modified by HNE and HHE which could be critical in the development of oxidative pathologies.
It is therefore imperative to understand the detoxification of HNE. We have found that HNE can be metabolized by conjugation with GSH (catalyzed by glutathione-S-transferase), reduced by aldose reductase and oxidized by aldehyde dehydrogenase (ALDH). Using antisense and SiRNA specific to various isozymes of ALDH as well as knock out mice, our studies show that ALDH1 is the main isozyme involved in the oxidation of HNE. Structural and kinetic studies on ALDH1 are underway to develop specific activators of this enzyme ---- an approach which will be therapeutic towards preventing oxidative pathologies.