Mentoring and Research in Mouse Models of Cancer and Infertility

描述(申请人提供)：首席调查员是一名委员会认证的解剖病理学家，长期研究人类疾病，特别是癌症和不孕不育的转基因小鼠模型的产生和特征。该奖项将为首席研究员提供受保护的时间，以便继续和延长他对初级研究员、临床研究员、住院医生、博士后和博士后研究员、医学生和本科生在老鼠病理生物学研究方面的指导和培训。此外，该奖项将允许首席研究员与具有不同研究兴趣的实验室合作，包括癌症、衰老、不孕不育和发育。这些合作将进一步加强首席调查员自己在小鼠病理生物学模型方面的知识基础和经验，并为培训广泛的小鼠病理生物学研究人员提供额外的机会。最后，这一奖项将允许首席调查员继续努力，进一步将小鼠发展为生殖道病理生物学研究的可行研究模型。我们将研究最近发现的肿瘤抑制基因Lkb1在正常生殖道功能和疾病中的作用。关于Lkb1是一种重要的生长抑制因子以及Lkb1缺乏促进生殖道癌变的假设将通过以下具体目的来探索：1)我们将有条件地删除男性生殖系中的Lkb1基因。这将使我们能够评估Lkb1在男性生殖系生理学和睾丸生殖细胞肿瘤中的生物学功能；2)为了探讨Lkb1在女性生殖系中的作用，包括它在卵子发生、生殖细胞肿瘤、卵泡成熟和不育中的作用，我们将研究Lkb1在卵母细胞中失活的功能后果；3)为了建立一种替代的、可能更容易处理的晚期子宫内膜癌小鼠模型，我们将建立一种转基因Lkb1缺陷子宫内膜的异位移植模型。这些研究将产生小鼠模型，这些模型将有助于1)识别和执行详细的分析与生殖道癌变有关的遗传损伤，2)在活动物的背景下研究相关的相互作用的生物因素，以及3)作为测试新的治疗靶点的临床前模型。该计划将促进首席调查员在其未来研究目标不可或缺的领域的专业知识，并为首席调查员自己的实验室的小鼠病理生物学初学者提供额外的培训机会。

DESCRIPTION (provided by applicant): 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.