Mentoring and Research in Mouse Models of Cancer and Infertility

描述（由申请人提供）：主要研究者是一名委员会认证的解剖病理学家，长期研究人类疾病（特别是癌症和不育症）的转基因小鼠模型的生成和表征。该奖项将为主要研究者提供受保护的时间，以继续和延长他对小鼠病理生物学研究中的初级研究者、临床研究员、住院医生、博士前和博士后研究员、医学生和本科生的指导和培训。此外，该奖项将允许主要研究者与具有不同研究兴趣的实验室进行合作，包括癌症，衰老，不孕症和发育。这些合作将进一步扩大主要研究者自己的知识基础和小鼠病理生物学模型的经验，并为培训广泛的小鼠病理生物学研究研究人员提供额外的机会。最后，该奖项将允许主要研究者进一步努力将小鼠作为生殖道病理学研究的可行研究模型。我们将研究最近发现的肿瘤抑制因子Lkb 1在正常生殖道功能和疾病中的作用。Lkb 1是一个重要的生长抑制因子，Lkb 1缺乏会促进生殖道癌的发生，这一假说将通过以下具体目标进行探讨：1）我们将有条件地删除男性生殖系中的Lkb 1基因。2）为了探讨Lkb 1在女性生殖系中的作用，包括其在卵子发生、生殖细胞肿瘤、卵泡成熟和不育中的作用，我们将研究Lkb 1在卵母细胞中失活的功能后果; 3）为了产生一种替代的和潜在的更易处理的晚期子宫内膜癌小鼠模型，我们将开发一种遗传修饰的Lkb 1缺陷型子宫内膜异位移植模型。这些研究将产生小鼠模型，这些模型将用于1）识别和详细分析在生殖道致癌作用中协同作用的遗传病变，2）在活体动物的背景下研究相关的相互作用生物因子，3）作为临床前模型用于测试新的治疗靶点。该计划将进一步促进主要研究者在其未来研究目标不可或缺的领域的专业知识，并为主要研究者自己实验室的小鼠病理生物学研究人员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.