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.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Midcareer Investigator Award in Biomedical and Behavioral Research (K26)
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National Center for Research Resources Initial Review Group (RIRG)
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Mirochnitchenko, Oleg
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University of Texas Sw Medical Center Dallas
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United States
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Goertz, Meredith J; Wu, Zhuoru; Gallardo, Teresa D et al. (2011) Foxo1 is required in mouse spermatogonial stem cells for their maintenance and the initiation of spermatogenesis. J Clin Invest 121:3456-66
Strauss, Tamara J; Castrillon, Diego H; Hammes, Stephen R (2011) GATA-like protein-1 (GLP-1) is required for normal germ cell development during embryonic oogenesis. Reproduction 141:173-81
Lynn, Kristi D; Udugamasooriya, D Gomika; Roland, Christina L et al. (2010) GU81, a VEGFR2 antagonist peptoid, enhances the anti-tumor activity of doxorubicin in the murine MMTV-PyMT transgenic model of breast cancer. BMC Cancer 10:397
Arnold, Shanna A; Rivera, Lee B; Miller, Andrew F et al. (2010) Lack of host SPARC enhances vascular function and tumor spread in an orthotopic murine model of pancreatic carcinoma. Dis Model Mech 3:57-72
Wingo, Shana N; Gallardo, Teresa D; Akbay, Esra A et al. (2009) Somatic LKB1 mutations promote cervical cancer progression. PLoS One 4:e5137
Dejean, Anne S; Beisner, Daniel R; Ch'en, Irene L et al. (2009) Transcription factor Foxo3 controls the magnitude of T cell immune responses by modulating the function of dendritic cells. Nat Immunol 10:504-13
Zhou, Wen; Cao, Qian; Peng, Yan et al. (2009) FoxO4 inhibits NF-kappaB and protects mice against colonic injury and inflammation. Gastroenterology 137:1403-14
John, George B; Shidler, Meredith J; Besmer, Peter et al. (2009) Kit signaling via PI3K promotes ovarian follicle maturation but is dispensable for primordial follicle activation. Dev Biol 331:292-9
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Kerdiles, Yann M; Beisner, Daniel R; Tinoco, Roberto et al. (2009) Foxo1 links homing and survival of naive T cells by regulating L-selectin, CCR7 and interleukin 7 receptor. Nat Immunol 10:176-84

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