The Principal Investigator is a board-certified anatomic pathologist with long-standing research interests in the generation and characterization of genetically-modified mouse models of human disease, particularly cancer and infertility. The award will provide the Principal Investigator with protected time with which to continue and extend his mentoring and training of beginning investigators, clinical fellows, residents, pre- and postdoctoral fellows, medical students, and undergraduates in mouse pathobiology research. Furthermore, this award will permit the Principal Investigator to engage in collaborations with laboratories with diverse research interests including cancer, aging, infertility, and development. These collaborations will further the Principal Investigator's own knowledge base and experience with mouse pathobiology models, and also provide additional opportunities for training a wide range of investigators in mouse pathobiology research. Lastly, this award will permit the Principal Investigator to extend efforts to further develop the mouse as a viable research model for reproductive tract pathobiology research. We will study the recently discovered tumor suppressor Lkb1 in normal reproductive tract function and disease. The hypothesis that Lkb1 is an important growth suppressor and that Lkb1 deficiency promotes carcinogenesis in the reproductive tract will be explored through the following specific aims: 1) We will conditionally delete theLkb1 gene in the male germline. This will permit us to assess the biological functions of Lkb1 both in male germline physiology and testicular germ cell neoplasia;2) To explore the role of Lkb1 in the female germ line including its roles in oogenesis, germ cell tumors, follicle maturation, and infertility, we will study the functional consequences of Lkb1 inactivation in oocytes;3) To generate an alternative and potentially more tractable mouse model of advanced endometrial cancer, we will develop a heterotopic transplantation model of genetically-modified Lkb1-deficient endometrium. These studies will result in mouse models that will be useful to 1) identify and perform detailed analyses of the genetic lesions that cooperate in reproductive tract carcinogenesis, 2) study the relevant interacting biological factors in the context of a living animal, and 3) serve as a preclinical models for testing of novel therapeutic targets. This program will further the Principal Investigator's expertise in an area integral to his future research goals and also provide additional training opportunities for beginning mouse pathobiology investigators in the Principal Investigator's own laboratory.
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