Dr. Boivins's immediate career objectives are to excel in primary and collaborative research efforts, to start a fellowship program in Mouse Pathology, and a training program in Laboratory Animal Medicine. This proposal will alleviate service work so that the fellowship and training program can be pursued and will provide funding for developing a primary research focus. Training and mentoring of high school students, undergraduates, graduate students, postdoctoral fellows, and faculty members will also continue to be performed in two general categories: unstructured or one-on-one time and structured time spent in courses or classes. Alleviation of service work will allow expansion in these areas. ? ? Lung cancer is the most common malignant tumor worldwide and is subsequently the greatest cause of cancer-related mortality. The identification of genes mutated in lung cancer has pointed to some of the signal transduction abnormalities, such as changes in RAS signaling, that occur in the establishment of these tumors. Additionally, mouse-modeling experiments have shown that transgenic mice over expressing Fgf-7, Fgf-10, or activated K-Ras in lung epithelium exhibit epithelial hyperplasia, adenoma, and carcinoma, respectively. Preliminary data have shown that tumor formation in the mouse can be promoted by altering the genotype of mice at the BIm locus. The experiments proposed here will establish and validate mouse models of lung cancer by manipulating the genetic background of the mouse to increase the expression of tumor-promoting factors by increasing somatic recombination and mutation. Tumors will be characterized genomically and by transcription profiling in order to identify other genes altered in the lung tumor formation. This work will test the hypothesis that haploinsufficiency of BIm will increase tumor progression in transgenic mouse models of lung tumorigenesis by increasing mutation rates. The long term aims are to establish in vivo models of lung neoplasia in the mouse in order to identify and characterize the signaling pathways and genes that are disrupted in the development of these tumors, to use these models to identify early markers of tumor development in the lung, and to identify therapeutic targets for human lung cancer therapy.