Vanderbilt University

2005 Highlights

  • Continued Studies in Oxidative Stress
  • Neurotoxicity
  • Mass Spectrometry and Proteomics Technology Development

    • Continued Studies in Oxidative Stress
    One area of emphasis in this Core Center is the study of oxidative stress and damage. Oxidative stress is an important component of the response to many environmental stresses, both chemical and physical agents, and is implicated in a number of chronic diseases. A case can be made that intervention is possible and practical. The program has been developed in the past several years through recruitments, development of facility cores and instrument acquisition, development of mechanisms of interaction, and (with the support of NIEHS) a new program project in this area (NIH P01 ES013125, PI: N. Porter). Center Investigators involved in these efforts include Drs. Burk, Liebler, Marnett, Morrow, Porter, and Rizzo (with Porter, Marnett, Morrow and Liebler having projects in the program project).

    The work spans understanding the fundamental chemistry of events in lipid peroxidation, the biochemistry of reactions of reactive oxygen and lipid peroxidation products with protein and DNA, and the biological effects of oxidative stress in in vitro and in vivo models. A key aspect of this program is the validation and use of biomarkers, e.g. isoprostanes, in both models and with human subjects. Another recent thrust is the development of antioxidants even more powerful than vitamin E. The following list of references includes some of the various diseases under investigation by these Center Investigators and their collaborators. Diseases (and related problems) on which research (with humans) has been published in the period 2004-2005 include atherosclerosis, ovarian cancer, colon cancer, Type 2 diabetes, aging, Alzheimer’s disease, inflammation, hyperthermia, renal disease, obesity, and infertility.

    Selected Publications

    • Morrow, J.D. (2005) Arterioscler Thromb Vasc Biol 25, 279-86. “Quantification of isoprostanes as indices of oxidant stress and the risk of atherosclerosis in humans.”
    • Musiek, E.S., Milne, G.L., McLaughlin, B., and Morrow, J.D. (2005) Brain Pathol 15, 149-58. “Cyclopentenone eicosanoids as mediators of neurodegeneration: a pathogenic mechanism of oxidative stress-mediated and cyclooxygenase-mediated neurotoxicity.”
    • Rouzer, C.A., Jacobs, A.T., Nirodi, C.S., Kingsley, P.J., Morrow, J.D., and Marnett, L.J. (2005) J Lipid Res 46, 1027-37. “RAW264.7 cells lack prostaglandin-dependent autoregulation of tumor necrosis factor-alpha secretion.”
    • Quinn, J.F., Montine, K.S., Moore, M., Morrow, J.D., Kaye, J.A., and Montine, T.J. (2004) J Alzheimers Dis 6, 93-7. “Suppression of longitudinal increase in CSF F2-isoprostanes in Alzheimer’s disease.”
    • Yin, H., Morrow, J.D., and Porter, N.A. (2004) J Biol Chem 279, 3766-76. “Identification of a novel class of endoperoxides from arachidonate autoxidation.”
    • Yin, H., Musiek, E.S., Gao, L., Porter, N.A., and Morrow, J.D. (2005) J Biol Chem 280, 26600-11. “Regiochemistry of neuroprostanes generated from the peroxidation of docosahexaenoic acid in vitro and in vivo.”
    • Musiek, E.S., Cha, J.K., Yin, H., Zackert, W.E., Terry, E.S., Porter, N.A., Montine, T.J., and Morrow, J.D. (2004) J Chromatogr B Analyt Technol Biomed Life Sci 799, 95-102. “Quantification of F-ring isoprostane-like compounds (F4-neuroprostanes) derived from docosahexaenoic acid in vivo in humans by a stable isotope dilution mass spectrometric assay.”
    • West, J.D., Ji, C., Duncan, S.T., Amarnath, V., Schneider, C., Rizzo, C.J., Brash, A.R., and Marnett, L.J. (2004) Chem Res Toxicol 17, 453-62. “Induction of apoptosis in colorectal carcinoma cells treated with 4-hydroxy-2-nonenal and structurally related aldehydic products of lipid peroxidation.”

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    Neurotoxicity
    Another growing area of investigation in the NIEHS is neurotoxicity, particularly as related to certain metals in the environment but also including new work on other chemicals and on developmental neurotoxicity. Center Investigators involved in this effort at this time include Drs. Aschner and Valentine (and, to a lesser extent, Dr. Burk). The work includes studies with several organic chemicals, manganese, and mercury. Basic mechanisms include metal transport, oxidative stress (see previous research highlight), and development of imaging methods. In this latter aspect, a pilot project awarded to Dr. Fitsanakis has been useful in the overall strategy. Further efforts in this area have involved the interactions with a series of non-Center faculty to develop the program. Some of the work (Dr. J. Aschner) involves neonatal infants receiving high measured amounts of manganese by standard perenteral nutrition schedules, and these infants are being monitored for changes related to hypothesized mechanisms of toxicity (Dr. J. Aschner joined the Core Center in 2007). These and other efforts are being developed and discussed for a planned NIEHS Superfund grant application to be submitted in early 2008, with metals, neurotoxicity, and genomic analysis of the factors of resistance and susceptibility proposed as major components of the program.

    Selected Publications

    • Aschner, M., Erikson, K.M., and Dorman, D.C. (2005) Crit Rev Toxicol 35, 1-32. “Manganese dosimetry: species differences and implications for neurotoxicity.”
    • Fitsanakis, V.A., Piccola, G., Aschner, J.L., and Aschner, M. (2005) Neurotoxicology “Characteristics of manganese (Mn) transport in rat brain endothelial (RBE4) cells, an in vitro model of the blood-brain barrier.”
    • Ichihara, G., Li, W., Shibata, E., Ding, X., Wang, H., Liang, Y., Peng, S., Itohara, S., Kamijima, M., Fan, Q., Zhang, Y., Zhong, E., Wu, X., Valentine, W.M., and Takeuchi, Y. (2004) Environ Health Perspect 112, 1319-25. “Neurologic abnormalities in workers of a 1-bromopropane factory.”

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    Mass Spectrometry and Proteomics Technology Development
    A third development in this NIEHS Core Center has been the development of mass spectrometry/proteomics technology, with two of the important techniques being direct imaging of whole tissues (both animal and human) and plasma profiles by these methods. The work is being led by two Center Investigators, Drs. Caprioli and Liebler. Some of the papers and reviews are listed below.
    Methods are being developed to address a number of disease states, including aspects related to environmental exposures, in experimental animals and humans. The plasma work is obviously non-invasive, but the work with most human tissues is necessarily invasive. Most of the studies to date are with human tumor or diseased tissue samples, and a list of the diseases already being addressed includes prostate, lung, brain, and colon cancer, bronchial disease, and glomerulosclerosis. A major goal of the research is the discovery of new biomarkers, which can then in many cases be monitored by other, less invasive markers. Another goal of the discovery phase of this work is the development of mechanisms and hypotheses.

    Selected Publications

    • Ma, S., Hill, K.E., Burk, R.F., and Caprioli, R.M. (2005) J Mass Spectrom 40, 400-4. “Mass spectrometric determination of selenenylsulfide linkages in rat selenoprotein P.”
    • Zimmerman, L.J., Wernke, G.R., Caprioli, R.M., and Liebler, D.C. (2005) J Proteome Res 4, 1672-80. “Identification of protein fragments as pattern features in MALDI-MS analyses of serum.”
    • Chaurand, P., Sanders, M.E., Jensen, R.A., and Caprioli, R.M. (2004) Am J Pathol 165, 1057-68. “Proteomics in diagnostic pathology: profiling and imaging proteins directly in tissue sections.”
    • Chaurand, P., Schwartz, S.A., and Caprioli, R.M. (2004) J Proteome Res 3, 245-52. “Assessing protein patterns in disease using imaging mass spectrometry.”

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