A novel mouse model of testicular granulosa cell tumors

一种新型小鼠睾丸颗粒细胞瘤模型

• 批准号: 10062490
• 负责人: Qinglei Li
• 金额: $ 7.31万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10062490
• 关键词: Address; Age; Animal Model; Biological Assay; Cell Differentiation process; Cells; Characteristics; Complement Factor B; Coupled; Development; Diagnostic; Disease; Embryonic Development; Etiology; FOXL2 gene; Genetic; Goals; Gonadal structure; Growth Factor; Human; Incidence; Light; Link; MADH2 gene; Malignant - descriptor; Malignant Neoplasms; Mission; Molecular; Mus; Mutation; Ovarian Granulosa Cell Tumor; Pathogenesis; Pathway Analysis; Pathway interactions; Patients; Phenotype; Prognosis; Proteomics; Publishing; Regulator Genes; Reporting; Research; Research Design; Role; Scientist; Sex Cord-Gonadal Stromal Tumors; Signal Transduction; Somatic Cell; Survival Rate; Testing; Testis; Therapeutic; Therapeutic Intervention; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; Transforming Growth Factors; Tumor stage; Validation; base; comparative; design; gene discovery; gene function; granulosa cell; granulosa cell tumor; insight; male; member; mouse model; novel; novel diagnostics; novel therapeutic intervention; programs; receptor; reproductive; sertoli cell; stem cells; transcriptomics; transdifferentiation; tumor; tumorigenesis

Title: A novel mouse model of testicular granulosa cell tumors PROJECT SUMMARY Despite the relatively high 5-year survival rate of granulosa cell tumors (GCTs) in stage I patients, poor prognosis is associated with patients at advanced tumor stage, justifying the need to study this type of poorly defined tumors. Of note, GCTs may also arise from the testis with low incidence. Thus, animal models are useful to investigate the pathogenesis of this disease. Overactivation of transforming growth factor β (TGFβ) receptor 1 (TGFBR1) using Amhr2-Cre to target mouse granulosa cells provokes the development of ovarian GCTs. It was found that male mice develop testicular GCTs at an early age. The exciting phenotypic manifestation of GCTs in the testes of these mice raised the question of how dysregulated TGFβ signaling promotes testicular GCT formation. The central hypothesis is that dysregulation of TGFβ signaling alters the differentiation program of Sertoli cells, promoting the transdifferentiation of Sertoli cell to malignant granulosa cells characteristic of GCTs. This hypothesis is based on compelling genetic evidence, and will be tested in a single aim by identifying mechanistic underpinnings of testicular GCT development resulting from constitutive activation of TGFBR1. A comprehensive approach combining transcriptomic and proteomic analyses will be utilized to address the posed question. Results of this application are expected to provide a paradigm shift for understanding gonadal tumorigenesis and reveal a novel link among growth factor signaling, cell fate alteration, and oncogenesis. Therefore, completion of this proposal will have a significant impact on the etiology of testicular GCTs. The findings have potential diagnostic and therapeutic value for sex cord-stromal tumors.

标题：一种新的睾丸颗粒细胞瘤小鼠模型 项目总结 尽管I期颗粒细胞瘤(GCTS)的5年生存率相对较高 患者中，预后不良的患者与晚期肿瘤患者相关，证明有必要 来研究这种界限不清的肿瘤。值得注意的是，GCTS也可能起源于睾丸 发病率低。因此，动物模型对于研究这种疾病的发病机制是有用的。 用Amhr2-Cre过度激活转化生长因子β受体1(TGFBR1) 靶向小鼠颗粒细胞刺激卵巢GCTS的发育。结果发现， 雄性小鼠在很小的时候就出现了睾丸GCTS。令人兴奋的表型表现 这些小鼠睾丸中的GCTs提出了一个问题，即转化生长因子β信号的失调是如何 促进睾丸GCT的形成。中心假说是转化生长因子β的调节失调 信号改变支持细胞的分化程序，促进细胞转分化 支持细胞向恶性颗粒细胞转化是GCTS的特征。这一假设是基于 令人信服的遗传证据，并将通过识别机械性的单一目标进行测试 TGFBR1的结构性激活是睾丸GCT发育的基础。 将利用结合转录组和蛋白质组分析的综合方法来 回答提出的问题。这一应用的结果预计将带来范式的转变 为了了解性腺肿瘤的发生并揭示生长因子信号之间的新联系， 细胞命运的改变和肿瘤的发生。因此，完成这项提案将有一个 对睾丸GCTS的病因有重大影响。这些发现具有潜在的诊断和 性索间质瘤的治疗价值。