Implementation Stage

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Implementation Pilot Project #1: Spatiotemporal dynamics of circadian rhythms of gene expression in prostate cancer Project PI: Alec J. Davidson Ph.D., Assistant Professor, Morehouse School of Medicine Project PI: Chia-Ling Hsieh, Ph.D., Assistant Professor, Emory School of Medicine Abstract Circadian rhythmicity provides a critically important temporal framework for many molecular, cellular and organismal functions. Until recently, it was thought that circadian rhythms in mammals were generated by a single 'master oscillator' in the brain, the SCN. We now know that virtually all cells and tissues have molecular machinery capable of generating circadian rhythms. Several recent reports suggest that experimental manipulation of host circadian rhythmicity affects tumor growth and mortality in rodents with cancer. In humans there are indications that altered circadian rhythmicity correlates with risk of cancer and with survival statistics in diagnosed patients. Therefore, the role played by circadian rhythms in host and tumor cells in the development and progression of cancer is of great interest. Prostate cancer is the second leading cause of cancer-related death in men in the United States [35]. Furthermore, prostate cancer represents one of the largest racial disparities among all risks to health. Better treatment approaches and mechanistic insight regarding the development and progression of this disease are of high value to both the scientific community and to society. Restricted feeding schedules synchronize circadian rhythms in behavior, physiology and gene expression in digestive organs and were also shown to inhibit growth of Glasgow osteosarcoma and to slow associated mortality in mice. Therefore, we propose a project to develop a better understanding of the impact of restricted feeding schedules on cancer development and progression, and on tumor rhythmicity in the prostate gland. We will develop a new mouse model and new cell lines to study the role of molecular circadian rhythms in the ontogeny and progression of prostate cancer. Mice will be generated that express mPer2Luc, a bioluminescent circadian reporter gene, and TRAMP, a prostate-specific viral oncogene, so that molecular rhythmicity can be assessed in real-time from benign and malignant tissue of every stage of cancer progression. Furthermore, we will develop new prostatic cell lines that express circadian reporter genes, so that prostate cancer bioluminescence driven by the circadian clock can be visualized non-invasively in vivo. These approaches together form an experimental tour de force that can be used to generate significant new insight into the roles played by circadian rhythmicity in prostate cancer and will address the hypothesis that rhythmicity in peripheral structures is intimately related to the organism's ability to combat the development and progression of cancer. The experiments will form the basis for future study of the mechanisms by which circadian rhythms influence the development of this and other cancers.