Mentoring and Research in Mouse Models of Cancer and Infertility

癌症和不孕不育小鼠模型的指导和研究

• 批准号: 7490558
• 负责人: DIEGO H CASTRILLON
• 金额: $ 12.03万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7490558
• 关键词: Age; Alleles; Anatomy; Animals; Area; Award; Basic Science; Biological; Biological Factors; Biological Process; Cancer Biology; Cell Cycle; Cells; Clinical; Clinical Investigator; Collaborations; Development; Disease; Embryo; Endometrial; Endometrial Carcinoma; Endometrium; Female; Future; Generations; Genes; Genetic; Germ Cells; Germ Lines; Germ cell tumor; Goals; Greater sac of peritoneum; Growth; Heterotopic Transplantation; Immunocompromised Host; In Vitro; Individual; Infertility; Laboratories; Lesion; Life; Malignant Neoplasms; Malignant neoplasm of testis; Medical Students; Mentors; Metabolic Pathway; Metabolism; Modeling; Mus; Neoplasms; Oocytes; Oogenesis; Organ; Ovary; Pathologist; Pathway interactions; Phosphotransferases; Physiological; Physiology; Postdoctoral Fellow; Pre-Clinical Model; Principal Investigator; Protein Biosynthesis; Protein Kinase; Proteins; Range; Research; Research Personnel; Role; Signal Pathway; Spermatogenesis; Suppressor Genes; Testing; Time; Tissues; Training; Translations; Tumor Suppressor Genes; Tumor Suppressor Proteins; base; carcinogenesis; cell type; experience; genetic analysis; human FRAP1 protein; human disease; improved; in vivo; insight; interest; knowledge base; male; mouse model; novel; novel therapeutics; null mutation; oocyte maturation; programs; reproductive; size; therapeutic target; tumor progression

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.

描述（由申请人提供）：首席研究员是一位经过委员会认证的解剖病理学家，长期研究人类疾病（特别是癌症和不孕症）转基因小鼠模型的生成和表征。该奖项将为首席研究员提供受保护的时间，以继续和扩大他对小鼠病理学研究领域的初级研究员、临床研究员、住院医师、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，该奖项将使首席研究员能够与具有不同研究兴趣（包括癌症、衰老、不孕不育和发育）的实验室进行合作。这些合作将进一步丰富首席研究员在小鼠病理生物学模型方面的知识基础和经验，并为培训小鼠病理生物学研究领域的广泛研究人员提供额外的机会。最后，该奖项将使首席研究员能够进一步努力进一步开发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抑癌基因Lkb1在正常生殖道功能和疾病中的作用。 Lkb1是一种重要的生长抑制因子以及Lkb1缺乏会促进生殖道癌变的假设将通过以下具体目标进行探索：1）我们将有条件地删除雄性种系中的Lkb1基因。这将使我们能够评估 Lkb1 在男性生殖细胞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在雌性生殖系中的作用，包括其在卵子发生、生殖细胞肿瘤、卵泡成熟和不孕中的作用，我们将研究卵母细胞中Lkb1失活的功能后果； 3）为了产生一种替代的、可能更容易处理的晚期子宫内膜癌小鼠模型，我们将开发一种转基因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）识别和详细分析与生殖道癌发生有关的遗传病变，2）研究活体动物中相关的相互作用的生物因素，3）作为测试新治疗靶点的临床前模型。该计划将进一步提高首席研究员在其未来研究目标不可或缺的领域的专业知识，并为首席研究员自己的实验室中的小鼠病理生物学研究新手提供额外的培训机会。