Caloric restriction causes a reduction in the incidence, and a delay in the onset time of cancer in mice. Caloric restriction has also been shown to increase longevity in primates, mice, C. elegans, Drosophila, and yeast. Results in these model organisms suggest that various histone deacetylases have different sets of target genes and different specificities for acetylated histones that either activate or inactivate the chromatin on these genes. Caloric restriction causes decreases in energy intake, energy expenditure, and body fat, but recent experiments show that Insulin-Receptor knockout mice have increases in energy intake, energy expenditure, and, paradoxically, longevity. These studies suggest that body fat and dietary fat are more meaningful than energy intake or expenditure as determinants of longevity and cancer progression. The main hypothesis of this proposal, based on the above observations, is that low body fat and dietary fat alters the chromatin state of key cancer genes such that the propensity for cancer decreases, and conversely, high body and dietary fat alters the chromatin state of key cancer genes such that the propensity for cancer increases. A secondary hypothesis is that these key genes are conserved between mice and Drosophila, and that a comparison of the genes whose chromatin is affected in a similar manner in these two organisms will help to identify the prostate-cancer susceptibility genes in humans.
The Aims are: 1) To identify genes with altered chromatin states (altered Rpd3 or Sir2 binding sites) in a multi-generational study in which high or low body fat isogenic strains of Drosophila are fed a low fat (high carbohydrate) or a high fat (American Blend Fat, low carbohydrate) diet; 2) To determine whether reducing the amount of Hsp90, Src, Rpd3, Sir2 and some of the Drosophila genes identified in Aim 1 alter the lifespan and the chromatin pattern of flies fed a low fat or high fat diet; and 3) To characterize the chromatin pattern (DNA methyiation, histone acetylation and methylation) of the telomerase gene, and of some of the homologs of the genes identified in Aim 1, in a mouse model of prostate cancer fed either an isocaloric low fat (high carbohydrate) or high fat diet at either 24 degrees C (a condition in which energy must be expended to maintain body temperature) or 35 degrees C (a thermoneutral temperature for mice). Upon completion of this proposal, with the judicious use of comparative Drosophila genetics, some of the genes with chromatin alterations that affect the propensity for cancer and lifespan in Drosophila, mice, and humans will be identified.
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