Research Interests

My major research interest is in the physiological and toxicological role of lipid peroxidation, in particular the electrophilic end product 4-hydroxynonenal (4-HNE). The work includes the elucidation of the catalytic mechanism of 4-HNE conjugation with glutathione by a glutathione transferase (murine mGSTA4-4) highly specialized for this reaction. A major emphasis of our work is on the biological role of 4-HNE. We generated a knockout mouse that lacks mGSTA4-4, and are studying the resulting phenotypic changes which, surprisingly, include obesity. In addition, in an extension of the free radical/oxidative damage theory of aging, we hypothesized that accumulation of proteins modified by electrophilic aldehydes such as 4-HNE contributes to senescence. Accelerated aging could be due to generalized organismal loss of homeostasis, or to interference by 4-HNE with specific longevity-assurance mechanisms. We confirmed the hypothesis that electrophilic damage contributes to aging in invertebrate models (the nematode C. elegans and the insect D. melanogaster). Overall, our results show that 4-HNE, which is cyto- and genotoxic at superphysiological concentrations, is a signaling molecule which modulates a variety of cellular and organismal functions.

Selected Publications:

Singh, S.P., Janecki, A.J., Srivastava, S.K., Awasthi, S., Awasthi, Y.C., Xia, S.J. and Zimniak, P. (2002).  Membrane association of glutathione S-transferase mGSTA4-4, an enzyme that metabolizes lipid peroxidation products.  J. Biol. Chem. 277: 4232-4239.

Engle, M.R., Singh, S.P., Czernik, P.J., Gaddy, D., Montague, D.C., Ceci, J.D., Yang, Y., Awasthi, S., Awasthi, Y.C. and Zimniak, P. (2004).  Physiological role of mGSTA4-4, a glutathione S-transferase metabolizing 4-hydroxynonenal: generation and analysis of mGsta4 null mouse.  Toxicol. Appl. Pharmacol. 194: 296-308.

Ayyadevara, S., Dandapat, A., Singh, S.P., Benes, H., Zimniak, L., Shmookler Reis, R.J. and Zimniak, P. (2005).  Lifespan extension in hypomorphic daf-2 mutants of Caenorhabditis elegans is partially mediated by glutathione transferase CeGSTP2-2.  Aging Cell 4: 299-307.

Ayyadevara, S., Engle, M.R., Singh, S.P., Dandapat, A., Lichti, C.F., Benes, H., Shmookler Reis, R.J., Liebau, E. and Zimniak, P. (2005).  Lifespan and stress resistance of Caenorhabditis elegans are increased by expression of glutathione transferases capable of metabolizing the lipid peroxidation product 4-hydroxynonenal.  Aging Cell 4: 257-271.

Singh, S.P., Chen, T., Chen, L., Mei, N., McLain, E., Samokyszyn, V., Thaden, J.J., Moore, M.M. and Zimniak, P. (2005).  Mutagenic effects of 4-hydroxynonenal triacetate, a chemically protected form of the lipid peroxidation product 4-hydroxynonenal, as assayed in L5178Y/Tk^+/- mouse lymphoma cells.  J. Pharmacol. Exp. Ther. 313: 855-861.

Ayyadevara, S., Dandapat, A., Singh, S.P., Siegel, E.R., Shmookler Reis, R.J., Zimniak, L. and Zimniak, P. (2006).  Life span and stress resistance of Caenorhabditis elegans are differentially affected by glutathione transferases metabolizing 4-hydroxynon-2-enal.  Mech. Ageing Dev. in press.