The long-term goal of the candidate is to develop a research expertise and program in the contribution of cigarette smoke-induced oxidative stress to cancer. A multidisciplinary educational and mentoring program is proposed. This includes didactic courses in molecular epidemiology, genetics and related fields, and participation in workshops, professional conferences, and other training opportunities with a subject content in oxidative stress or molecular epidemiology. Mentorship will include hands-on training and research guidance under Dr. John Richie, an authority on glutathione and cancer prevention, and Dr. Philip Lazarus, Associate Director of the Penn State Cancer Center. There are few reliable epidemiologic markers of oxidative stress. To date proxy markers such as blood antioxidant vitamin levels and oxidative DMA or lipid damage has been used to study oxidative stress in cancer. However, such markers provide little information about changes in the redox status of cells and alterations in critical proteins involved in carcinogenesis. The oxidation of glutathione to protein-bound glutathiolation (GSSP) is proposed as a sensitive marker of oxidative stress. Our preliminary studies demonstrate substantial increases in GSSP in cigarette smokers. The central hypothesis is that cigarette smoke free radicals cause oxidative stress as measured by blood protein glutathiolation, and that GSSP levels are modified by polymorphisms in oxidative stress genes, antioxidants and lifestyle factors.
The specific aims are: 1. Determine racial differences in blood GSSP levels in response to cigarette-induced oxidative stress. Measure the effects of alcohol consumption, diet, MnSOD and HOGG1 genetic polymorphisms on blood GSSP levels. 2. Determine the risk of lung and oral cancer associated with blood GSSP concentrations in case-control studies. For lung cancer, determine the risk associated with the MnSOD polymorphism and its joint effect with GSSP. 3. Conduct a randomized intervention trial of MAC supplementation on blood and exfoliated buccal cell GSSP concentrations. Correlate levels of GSSP with markers of oxidative damage including 8-OhdG, F-2 isoprostanes, protein carbonyls, and plasma vitamin antioxidant levels. Determine the effects of MAC supplementation after adjustment for age, genetic polymorphisms and other factors.
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