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Ovulation, inclusion cysts, and p53 mutations in a mouse model of ovarian cancer

卵巢癌小鼠模型中的排卵、包涵囊肿和 p53 突变

基本信息

批准号：
7943114
负责人：
Joanna E Burdette
金额：
$ 7.85万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-29 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7943114
关键词：
A Mouse Alleles Animal Model Animals Applications Grants Benign Breast Feeding Carcinoma Cells Chemoprevention Chronic Contraceptive methods Contralateral Cortex of ovary Cyst Development Disease Dominant-Negative Mutation Endosalpingiosis Epithelial Epithelial Cells Epithelial cyst Epithelial ovarian cancer Epithelium Etiology Event Frequencies Future Injection of therapeutic agent Intervention Investigation Lactation Lesion Link Malignant - descriptor Malignant Neoplasms Malignant neoplasm of ovary Mammalian Oviducts Menopause Modeling Mullerian duct inhibiting substance Mus Mutate Mutation Neoplasm Metastasis Oral Oral Contraceptives Organ Ovarian Ovary Ovulation Pathway interactions Pharmaceutical Preparations Pregnancy Process Protein p53 Risk Role Serous Signal Transduction Superovulation Surface TP53 gene Testing Transgenes Tube Tumor Suppressor Genes Tumor Suppressor Proteins Woman cell transformation interest model development mouse model ovarian neoplasm prevent promoter recombinase reproductive response tool virus Cre recombinase

项目摘要

DESCRIPTION (provided by applicant): Ovarian cancer is the most lethal gynecological malignancy among western women. The etiology of ovarian cancer is unknown, but intervention that blocks ovulation reduces the risk for developing ovarian cancer. For example, pregnancy, breast-feeding, use of oral contraceptives, and early menopause all reduce the risk for developing ovarian cancers. Ovarian inclusions cysts are possible precursor lesions of ovarian cancer. Alternatively, ovarian cancers may arise in fallopian tubal epithelial cells. We have developed a Smad2 dominant negative (Smad2DN) mouse that develops epithelial-lined ovarian inclusions cysts that resemble the fallopian epithelium (endosalpingiosis). When these animals are chronically superovulated for six months, they develop significantly more ovarian inclusions cysts than their normal littermate counterparts that are ovulation suppressed, but these cysts never developed into cancer. We hypothesize that the transition of ovarian inclusion cysts to cancer is a two hit process. In at least three other models of ovarian cancer, the mutation of p53 is required for lesions to develop. We therefore propose to develop a Smad2DN/floxedp53 bitransgenic mouse to provide the first animal model to directly investigate the link between ovulation and the transition of ovarian inclusion cysts or tubal epithelial cells into cancers. Specific Aim 1 will investigate the presence of ovarian cancer at 6 and 12 months in Smad2DN mice with the floxed p53 allele deleted in the ovarian surface using cre-recombinase intrabursal injections. Specific Aim 2 will investigate ovarian cancer in Smad2DN/floxedp53 mice with the floxed p53 allele deleted in the tubal epithelium using cre-recombinase intratubal injections. Specific Aim 3 will then compare superovulated and ovulation suppressed Smad2DN/floxedp53 mice with p53 deleted in either the OSE or the tube to investigate increased formation of cancers in response to ovulation in animals that have both the Smad and p53 pathways inactivated. Development of this model will provide two pathways for further investigation critical in ovarian cancer, p53 and Smad signaling. The model will help explore if inactivation in the tube or the ovary contributes to serous cancers. Lastly, will be able to conduct future studies in this mouse model aimed at generating therapies that prevent ovarian cancer.

描述（由申请人提供）：卵巢癌是西方妇女中最致命的妇科恶性肿瘤。卵巢癌的病因尚不清楚，但阻断排卵的干预措施可降低患卵巢癌的风险。例如，怀孕、母乳喂养、口服避孕药的使用和绝经早期都可以降低患卵巢癌的风险。卵巢内含物囊肿可能是卵巢癌的先兆病变。或者，卵巢癌可能发生在输卵管上皮细胞中。我们已经开发了一种Smad 2显性阴性（Smad 2DN）小鼠，其产生类似于输卵管上皮的上皮内衬卵巢内含物囊肿（输卵管内膜炎）。当这些动物长期超数排卵6个月时，它们比排卵抑制的正常同窝动物产生更多的卵巢内含物囊肿，但这些囊肿从未发展成癌症。我们假设卵巢包涵体囊肿向癌的转变是一个两次打击的过程。在至少三种其他卵巢癌模型中，p53突变是病变发展所必需的。因此，我们建议开发一种Smad 2DN/p53双转基因小鼠，以提供第一个动物模型，直接研究排卵和卵巢包涵体囊肿或输卵管上皮细胞转化为癌症之间的联系。具体目标1将使用cre重组酶囊内注射研究卵巢表面缺失floxed p53等位基因的Smad 2DN小鼠在6个月和12个月时卵巢癌的存在。具体目标2将使用cre重组酶输卵管内注射研究输卵管上皮中缺失floxed p53等位基因的Smad 2DN/p53小鼠中的卵巢癌。然后，特定目标3将比较超排卵和排卵抑制的Smad 2DN/p53小鼠，其中在OSE或试管中缺失p53，以研究在具有Smad和p53途径失活的动物中响应于排卵的癌症形成增加。该模型的建立将为进一步研究卵巢癌中的两个关键信号通路p53和Smad信号通路提供依据。该模型将有助于探索输卵管或卵巢中的失活是否有助于浆液性癌。最后，将能够在这种小鼠模型中进行未来的研究，旨在产生预防卵巢癌的疗法。