Humans are exposed to a multitude of chemical (e.g. pollutants and drugs) and physical (e.g. radiation) agents in the environment that induce oxidative stress in most cell types that comprise tissues and organ systems. Oxidative stress, characterized by increased levels of reactive oxygen species (ROS), can induce both aberrant signal transduction and oxidative damage to cellular macromolecules, including lipids, proteins and nucleic acids. Such oxidative changes directly contribute to a variety of deleterious biological endpoints associated with several important human diseases, including cardiovascular and neurodegenerative disorders and cancer. Several lines of evidence have revealed links among oxidative stress, inflammation and the development of colon cancer. Colorectal cancer is the third most commonly diagnosed cancer and is the second leading cause of cancer death in the United States. Currently, we have a very poor understanding of the mechanisms by which oxidative stress mediates colon tumor development. The overall theme of this program project renewal is to delineate the pathogenic contributions of two major, stress-activated cellular generators of ROS (mitochondria and Nox) and to investigate the response pathways to ROS and to ROS-damaged macromolecules which directly lead to genetic instability and other biological changes that contribute to tumor development. This program of investigation builds from information obtained during the previous support period and is comprised of five complementary, synergistic projects that will employ two powerful eukaryotic model systems (yeast and mice) in order to define important elements of the eukaryotic/mammalian oxidative stress circuitry. These systems are genetically and biochemically tractable and will also provide an important mammalian intestinal tumor model that is relevant to human colon cancer development. The great advantage of employing such model systems is that key targets and system components (a number of which were identified and analyzed during the previous period of support) can be examined within the context of a battery of isogenic yeast strains, mammalian cells, and individual animals at a level of complexity and pace not yet achievable using human tissues and cells. The information generated from such studies can subsequently be directly and quickly translated into studies utilizing human material. Dissection of these cellular damages and response pathways will lead to a clearer understanding of the role of oxidative stress in colon cancer development and will reveal novel targets for prevention and intervention. BACKGROUND This is the first revision of a competitive renewal application for a Program Project grant that was initially funded in 2002. The overall theme of the initial proposal was to understand the interrelationships between the pathways that mediate resistance to DNA damage. The initial program consisted of five research projects. Yeast and bacterial systems were used as models. In the competitive renewal, the focus has been redirected toward colon cancer. Thus, the project that was directed by Dr. Bernard Weiss will be discontinued and replaced by a project directed by Dr. Lambeth. Based on the comments of the previous reviewers, the project by Dr. Siede has also been eliminated. Thus, the current application has four research projects. Dr. Shadel and Dr. Doetsch will direct two of the projects and the fourth project will be directed jointly by Drs. Kow and Crouse. In addition to the four research projects, there is an administrative core and a mouse tumor model and mammalian cell culture core. In the initial submission of the competitive renewal, 32 publications and manuscripts were listed as a direct result of the support provided by the program project grant. In this revised version, the number has increased to 51. The focus of the studies described in this revised application is to delineate the pathogenic contributions of the reactive oxygen species generated by the mitochondria and the Nox and the response pathways to ROS and ROS-damaged macromolecules which directly lead to genetic instability and other biological changes that contribute to tumor development. Yeast will still be used as a model system in combination with mammalian intestinal tumor models. PROGRAM AS AN INTEGRATED EFFORT
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