Understanding the origin,initiation,and progression of high-grade serous ovarian cancer

描述（由申请人提供）：卵巢癌是一种致命的疾病，因为大多数病例是在癌症已经转移的晚期诊断出来的。然而，目前没有有效的诊断或筛查测试可用于卵巢癌的早期发现。这种失败的主要原因是对这种癌症的早期肿瘤过程知之甚少。虽然被命名为“卵巢癌”，但最致命的类型，高级别浆液性卵巢癌（HGSC），似乎不是起源于卵巢，而是起源于输卵管。除了这个新兴的组织起源概念之外，大多数早期肿瘤机制仍然难以捉摸，这对开发有效的早期诊断或筛查测试构成了主要障碍。因此，本提案的总体目标是提高我们对致死性卵巢癌的分子机制的理解，特别是对HGSC的细胞起源、起始和进展的理解。Dicer-Pten双敲除（DKO）和p53-Dicer-Pten三突变（TKO）小鼠模型将显著重现致命的人类高级别浆液性卵巢癌，这将有助于拟议的研究。在指导的K99阶段，研究将侧重于使用和表征这些DKO和TKO模型。特别是，将使用DKO小鼠进行临床前试验，以及使用人类卵巢癌细胞系进行基于细胞的分析，以评估抗雌激素治疗晚期卵巢癌的治疗潜力。阐明HGSC的细胞起源和早期进展将需要通过小鼠遗传命运图谱分析进行细胞谱系追踪，这将从K99期开始，但在独立的R00期广泛进行。此外，我们将通过分析TKO小鼠，并在这一独立阶段产生多个p53双突变小鼠，来详细研究p53突变在HGSC的发生和早期进展中的作用。在从事这些项目的过程中，贝勒医学院，也是世界上最大的德克萨斯医学中心的一部分，为我的博士后培训和继续发展成为一名独立研究者提供了非凡的研究和学术环境。再加上我在卵巢生物学方面的深入博士培训，以及与相关专家建立的合作关系，我在卵巢癌小鼠模型开发和分析方面的丰富博士后研究经验，将使我能够追求和实现我所提出的研究目标。毫无疑问，这将导致一个成功的职业道路，作为一个独立的研究人员在癌症研究，重点是卵巢癌。更重要的是，我们将从这些拟议的研究中获得的知识将提供至关重要的翻译见解。不仅为卵巢癌的早期发现和筛查，也为晚期卵巢癌提供了新的治疗方法。

DESCRIPTION (provided by applicant): Ovarian cancer is a deadly disease because most cases are diagnosed at advanced stages, when the cancer has already metastasized. Yet no effective diagnostic or screening tests are currently available for the early detection of ovarian cancer. The main reason for this failure is that little has been known about the early tumor process of this cancer. Though named "ovarian cancer," the most deadly type, high-grade serous ovarian carcinoma (HGSC), appears to originate, not in the ovary, but instead in the fallopian tube. Beyond this emerging concept of tissue origin, yet most early tumor mechanisms still remain elusive, which poses a major roadblock to developing an effective diagnostic or screening test for early detection. Thus, the overall goal of this proposal is to improve our understanding on the molecular mechanisms of deadly ovarian cancer, especially the cell of origin, initiation, and progression of HGSC. Remarkably recapitulating deadly human high- grade serous ovarian cancer, the Dicer-Pten double-knockout (DKO) and p53-Dicer-Pten triple-mutant (TKO) mouse models will be instrumental in the proposed research. During the mentored K99 phase, the research will focus on employing and characterizing these DKO and TKO models. In particular, pre-clinical trials using DKO mice as well as cell-based assays using human ovarian cancer cell lines will be performed to evaluate the therapeutic potential of antiestrogen therapy in advanced ovarian cancer. Elucidating the cell of origin and early progression of HGSC will require cell-lineage tracing by mouse genetic fate-mapping analysis, which will begin in the K99 phase but be pursued extensively during the independent R00 phase. In addition, defining the role of p53 mutation in the initiation and early progression of HGSC will be investigated in detail by analyzing TKO mice and generating multiple p53 double-mutant mice during this independent phase. In pursuing these projects, Baylor College of Medicine, also part of the world-largest Texas Medical Center, offers extraordinary research and academic environments for my postdoctoral training and continuing development into an independent investigator. Coupled with my in-depth doctoral training in ovarian biology and also established collaborations with relevant experts, my extensive postdoctoral research experience in developing and analyzing mouse models of ovarian cancer will enable me to pursue and achieve the aims in the proposed research. This will undoubtedly lead to a successful career path as an independent investigator in cancer research with an emphasis on ovarian cancer. More important, the knowledge we will gain from these proposed studies will offer vital translational insights ? not only for the early detection and screening of ovarian cancer, but also for a new treatment for advanced ovarian cancer.