Gonadotropins & Cox-2 in Ovarian Cancer Prevention

促性腺激素

• 批准号: 8447386
• 负责人: XiangXi Mike Xu
• 金额: $ 35.35万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8447386
• 关键词: Accounting; Address; Age; Aging; Apoptosis; Aspirin; Basement membrane; Benign; Biological; Biology; Cancer Etiology; Cancer Model; Chemicals; Contraceptive Agents; Development; Devices; Dose; Enzymes; Epidemiology; Epithelial Cells; Etiology; Funding; Gene Dosage; Genetic; Genotype; Germ Cells; Goals; Gonadotropins; Growth; Hormones; Implant; Incidence; Infusion procedures; Investigation; Knock-out; Knowledge; Lead; Longevity; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Menopause; Modeling; Morphology; Mus; Mutant Strains Mice; Mutation; Oncogenic; Oral Contraceptives; Organ Culture Techniques; Ovarian; Ovarian Follicle; Ovary; Pathway interactions; Peptide Hydrolases; Phenotype; Physiology; Point Mutation; Post-Menopausal Hormone Replacement Therapy; Postmenopause; Prevention strategy; Preventive; Progesterone; Progestins; Protein Tyrosine Kinase; Proto-Oncogene Protein c-kit; Reagent; Reproductive History; Risk; Risk Factors; Role; Study models; Surface; System; Testing; Translating; Tubular Adenoma; Tumor Biology; Variant; White Spots; abstracting; adenoma; base; cancer risk; design; follow-up; inhibitor/antagonist; mouse model; mutant mouse model; neoplastic; null mutation; ovarian cancer prevention; ovarian neoplasm; practical application; premature; prevent; reproductive; research study; tumor; tumorigenesis

Project Summary/Abstract Epidemiological observations have established ovarian cancer risk factors, such as high cancer incidence in peri- postmenopausal ages and preventive activity of oral contraceptives. However, the mechanisms for these well-established ideas remain obscure, and experimental systems are highly desirable to gain biological and mechanistic understanding of the epidemiological findings. Menopausal ovaries undergo morphological changes, known as "ovarian aging" which are implicated in the high incidence of ovarian cancer occurring during the peri-menopausal and immediate post-menopausal periods. We explore a germ cell-deficient Wv (white spotting variant) mutant mouse line to model the impact of menopausal physiology on the increased risk of ovarian cancer, and the model may also allow us to test preventive agents. The Wv mice harbor a point mutation in c-Kit that reduces the tyrosine kinase activity to about 1-5% (not a null mutation). The mutation results in a premature loss of ovarian germ cells and follicles, but other biological phenotypes are very mild and the mice have a near normal life span. The germ cell- deficient Wv mice recapitulate some of these post-menopausal alterations in ovarian morphology and develop tubular adenomas. Furthermore, addition of oncogenic mutation such as loss of p27kip1 or loss of p53 converts the ovarian adenomas into neoplastic tumors. In preliminary experiments, suppression of Cox-1 was found to delay ovarian follicle depletion in addition to suppressing tumor development. Among several proteolytic enzymes investigated, we found that uPA was elevated in Wv ovaries, and we speculate that uPA may be the underlying cause of Wv ovarian tumor phenotype. The goal of the proposal is to use the Wv mouse models with additional oncogenic mutation to study the mechanisms responsible for the menopausal increase in ovarian cancer risk and to test several potential preventive approaches. First, we will further study the roles of Cox-1 in ovarian germ cell and follicle maturation and survival, and ovarian tumor development (Aim 1). We also will investigate the importance of uPA in ovarian tumor formation using the Wv mouse models, and the ability of uPA inhibitors to reduce ovarian tumorigenesis (Aim 2). Lastly, we will use progestin to suppress gonadotropins in Wv mice to verify the "follicle depletion hypothesis". The experiments will reveal whether follicle depletion or increased gonadotropins is the principal cause of ovarian tumorigenesis in Wv mice (Aim 3). These studies will address a fundamental mechanism of ovarian cancer etiology related to reproductive factors and the roles and mechanisms of Cox-1, Cox-2, uPA, and progestins (oral contraceptives), which are potential preventive targets/agents for ovarian cancer. Successful completion of the experiments will further our understanding of the underlying mechanism for reproductive factors on ovarian cancer risk and provide rationale for possible preventive approaches for ovarian cancer.

项目摘要/摘要 流行病学观察已经建立了卵巢癌危险因素，例如高癌 绝经后年龄和口服避孕药的预防活性的发病率。但是， 这些完善的想法的机制仍然晦涩难懂，实验系统非常可取 为了获得对流行病学发现的生物学和机械理解。 更年期卵巢发生形态学变化，称为“卵巢衰老”，与 卵巢癌的高发病率在绝经期和绝经后立即发生 时期。我们探索了生殖细胞缺陷的WV（白斑变体）突变小鼠系列，以建模 关于卵巢癌风险增加的更年期生理学，该模型也可能使我们能够测试 预防剂。 WV小鼠在C-KIT中具有点突变，将酪氨酸激酶活性降低到 约1-5％（不是无效突变）。该突变导致卵巢生殖细胞和卵泡过早丧失， 但是其他生物学表型非常温和，小鼠的寿命接近正常。生殖细胞 - 不足的WV小鼠概括了卵巢形态的这些绝经后改变并发展 管状腺瘤。此外，添加致癌突变，例如损失P27KIP1或p53丢失 将卵巢腺瘤转化为肿瘤肿瘤。在初步实验中，Cox-1的抑制是 发现除了抑制肿瘤发育外，还会延迟卵巢卵泡耗竭。在几个 研究了蛋白水解酶，我们发现UPA在WV卵巢中升高，我们推测UPA UPA 可能是WV卵巢肿瘤表型的根本原因。 该提案的目的是使用具有其他致癌突变的WV小鼠模型来研究 造成卵巢癌风险更年期增加的机制，并测试几种潜力 预防方法。首先，我们将进一步研究Cox-1在卵巢生殖细胞和卵泡中的作用 成熟和生存，以及卵巢肿瘤的发展（AIM 1）。我们还将调查 使用WV小鼠模型形成卵巢肿瘤的UPA，以及UPA抑制剂降低卵巢的能力 肿瘤发生（AIM 2）。最后，我们将使用孕激素抑制WV小鼠中的促性腺激素以验证 “卵泡耗尽假设”。实验将揭示卵泡耗竭或增加 促性腺激素是WV小鼠卵巢肿瘤发生的主要原因（AIM 3）。 这些研究将解决与生殖有关的卵巢癌病因的基本机制 Cox-1，Cox-2，UPA和孕激素（口服避孕药）的因素以及作用和机制， 卵巢癌的潜在预防靶标/药物。成功完成实验将进一步完成 我们对卵巢癌风险生殖因素的基本机制的理解，并提供 卵巢癌可能预防方法的理由。