This Project is the second of this Center and is entitled, "Stress Induced Changes in Nuclear Structure and Higher Order DNA Organization". Bacterial cells have developed a number of mechanisms to allow them to respond quickly to environmental stresses and evolve. The cancer cell has adapted many of these properties and is capable of surviving all forms of currently used treatments. In order to survive, cancer has reactivated the evolutionary process in somatic cells from a wide diversity of genotypic and functional cellular components that comprise the cancer population The hypothesis being tested is that the mechanisms of the stress induced phenotypic changes in cell and chromatin structure that play a critical role in evolution and how these processes are perturbed in the development and control of the therapeutic resistance in cancer. This hypothesis will be evaluated with the following specific aims: 1. to examine the molecular mechanisms of adaptive evolution by which stress induces changes in the re-organization of chromosome domains in prokaryotic and eukaryotic systems;2. to determine the alterations in the actual and functional proteomic composition of nuclear structural elements under stressed conditions;and 3. To examine the effects of stress on cellular motility in prokaryotic and eukaryotic systems. These studies should reveal novel insights into the process by which cancer undergoes punctuated evolution and develops resistant to all therapeutic approaches being utilized.
As pointed out several times in this Center, we have made little progress towards developing effective therapies for many cancer types. The studies outlined in this Project are critical to our understanding of how to get beyond the highly resistant nature of cancer cells by taking advantage of some of their diminished abilities to respond to microenvironmental stresses.
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