Mouse model for juvenile granulosa cell tumorogenesis

幼年颗粒细胞肿瘤发生的小鼠模型

• 批准号: 6710691
• 负责人: Rosemary W Steinemetz
• 金额: $ 7.53万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6710691
• 关键词: G protein coupled receptor kinase; SDS polyacrylamide gel electrophoresis; arrestins; biological signal transduction; carcinogenesis; cell proliferation; clinical research; disease /disorder model; follicle stimulating hormone; granulosa cell; hormone receptor; hormone regulation /control mechanism; laboratory mouse; neoplastic growth; ovary neoplasms; pathologic process; pediatric neoplasm /cancer; polymerase chain reaction; western blottings

DESCRIPTION (provided by applicant): The etiologic factors that are responsible for the development of ovarian granulosa cell tumor (GCTs) are poorly understood. Thus, targeted treatment for these tumors does not exist. Based on clinical and basic science data, the follicle stimulating hormone receptor (FSH-R) pathway may be involved in the pathogenesis of this disorder. We, and others, have examined GCTs for the presence of FSH-R mutations that would impart constitutive activity as well as screened tumors for Gsalpha mutations. Thus far, no mutations have been detected. However, other essential components of this pathway, such as the G protein-coupled receptor kinases (GRKs) and the arrestins have never been examined for abnormalities that might lead to hyperstimulation. In order to test the hypothesis that the FSH-R pathway is involved in GCT pathogenesis, we will utilize a unique mouse model for GCT formation. This proposal represents a new research direction for the principal investigator. The application is designed to generate pilot data to support a more comprehensive R01 application to investigate the pathogenesis of GCTs. In this pilot R03 proposal, we will validate the use of the SWXJ-9/SWR mouse as an appropriate model of GCTs in which detailed analysis of the FSH-R signaling pathway can be studied. This will be accomplished by pursuing three specific aims. First, we will characterize and compare GRK and arrestin expression in normal and malignant mouse granulosa cells. Next, we will compare FSH-R desensitization and internalization in these two cell types and determine which, if any, GRK and arrestin isoforms are essential for FSH-R signaling in normal and pathologic granulosa cells. Finally, we will dissect out the roles of gonadotropins and sex steroids for the development of GCTs, in vivo, using the animal model. Regardless of the outcome, it is anticipated that significant novel data will be generated from completion of this proposal that will direct more extensive future studies. Ultimately, this work has the potential to advance our understanding of the pathogenesis of GCTs, contributing to effective, targeted forms of therapy for this serious disorder of girls and women.

描述（由申请人提供）：对导致卵巢颗粒细胞瘤（GCT）发生的病因知之甚少。因此，针对这些肿瘤的靶向治疗并不存在。根据临床和基础科学数据，卵泡刺激素受体（FSH-R）途径可能参与该疾病的发病机制。我们和其他人检查了 GCT 是否存在会赋予组成性活性的 FSH-R 突变，并筛选了肿瘤的 Gsalpha 突变。到目前为止，尚未检测到突变。然而，该通路的其他重要组成部分，例如 G 蛋白偶联受体激酶 (GRK) 和抑制蛋白，从未被检查过是否存在可能导致过度刺激的异常。为了验证 FSH-R 通路参与 GCT 发病机制的假设，我们将利用独特的小鼠模型来观察 GCT 的形成。该提案代表了首席研究员的新研究方向。该应用程序旨在生成试点数据，以支持更全面的 R01 应用程序来研究 GCT 的发病机制。在这个试点 R03 提案中，我们将验证使用 SWXJ-9/SWR 小鼠作为 GCT 的适当模型，在其中可以研究 FSH-R 信号通路的详细分析。这将通过追求三个具体目标来实现。首先，我们将表征并比较正常和恶性小鼠颗粒细胞中 GRK 和抑制蛋白的表达。接下来，我们将比较这两种细胞类型中的 FSH-R 脱敏和内化，并确定哪些 GRK 和视紫红质抑制蛋白亚型对于正常和病理颗粒细胞中的 FSH-R 信号传导至关重要。最后，我们将使用动物模型在体内剖析促性腺激素和性类固醇在 GCT 发育中的作用。 无论结果如何，预计该提案的完成将产生重要的新数据，这将指导未来更广泛的研究。最终，这项工作有可能增进我们对 GCT 发病机制的理解，有助于为这种严重的女孩和妇女疾病提供有效、有针对性的治疗方法。