The role of fallopian tube microbiome in ovarian carcinogenesis

项目摘要/摘要 卵巢癌的发病机制至今仍存在根本性的认识空白。除了 由于卵巢癌易感基因的遗传性突变，大多数病例的直接原因尚不清楚。 缺乏对初始事件的了解阻碍了早期发现，预防，甚至 这种最致命的妇科恶性肿瘤的靶向治疗。本申请的总体目标是 研究导致卵巢癌的新途径，从而使未来的研究能够在发展中国家进行。 预防和治疗策略。卵巢癌发生的一个新的高度可信的中心假说 这里提出：某些生殖道细菌的上行感染导致输卵管炎症 和DNA损伤细胞导致卵巢癌。多项证据支持这一假设，例如 双侧输卵管结扎术和口服避孕药对卵巢癌的保护作用， 子宫内膜异位症相关的卵巢癌风险增加。然而，缺乏直接证据。 因此，将通过追求四个具体目标来测试这一假设：1）确定是否存在微生物组， 正常输卵管与诊断为卵巢癌的患者不同， 组织学; 2）确定子宫内膜异位症患者的输卵管微生物组是否与子宫内膜异位症患者的输卵管微生物组不同。 无子宫内膜异位症的女性; 3）比较BRCA 1突变患者的输卵管微生物组 没有癌症的人与有癌前病变的人;和4）比较 结扎输卵管伞端的正常输卵管上皮细胞与未闭输卵管上皮细胞的年龄差异 匹配的控制。大卫弗雷德里克博士的16 S rRNA基因测序技术已经很好地建立起来， 实验室，以及一个长期存在的卵巢癌和输卵管组织库，由伊丽莎白斯威舍博士指导 将在这个项目中使用。该建议是创新的，因为该假设是完全新颖的， 尽管它在生物学上是合理的，并且得到了以前研究的支持，但以前没有进行过测试。拟议 研究是重要的，因为通过收集直接证据，卵巢癌与改变输卵管 微生物组，它有望垂直推进和扩大我们对卵巢癌发病机制的理解， 癌症和输卵管的病理作用。最终，这种知识有可能减少 通过早期发现、预防或靶向治疗降低卵巢癌死亡率。在职业发展过程中 获奖期间，申请人将有充分的机会在翻译研究， 微生物学，基因组学和癌症生物学，这将开辟一条通往富有成效的研究生涯的道路， 最终实现通过科学发现改善女性健康的职业目标。

PROJECT SUMMARY/ABSTRACT There is a fundamental gap in understanding the pathogenesis of ovarian carcinoma. Other than inherited mutations in proven ovarian cancer susceptibility genes, the direct cause for most cases is unknown. The lack of understanding of the initiating events hampers efforts at early detection, prevention, and even targeted therapy of this most lethal gynecologic malignancy. The overall objective of this application is to investigate novel pathways leading to ovarian cancer, and thus enable future investigations in developing prevention and treatment strategies. A novel yet highly plausible central hypothesis for ovarian carcinogenesis is proposed here: ascending infection with some genital tract bacteria leads to inflammation in the fallopian tubes and DNA damage to cells resulting in ovarian cancer. Multiple pieces of evidence support this hypothesis, such as the protective effect of bilateral tubal ligation and oral contraceptives against ovarian cancer, and the increased risks of ovarian cancer associated with endometriosis. However, direct evidence is lacking. Therefore, this hypothesis will be tested by pursuing four specific aims: 1) To determine if the microbiome of normal fallopian tubes is different from patients with a diagnosis of ovarian carcinoma according to specific histology; 2) To determine if the fallopian tube microbiome in patients with endometriosis is different from that of women without endometriosis; 3) To compare the fallopian tube microbiome in patients with BRCA1 mutations who are cancer free with those who have premalignant alterations; and 4) To compare the transcriptomes of normal fallopian tube epithelial cells from the fimbrial ends of ligated tubes with those from patent tubes in age matched controls. The 16S rRNA gene sequencing technology that is well established in Dr. David Fredricks’ lab, and a long-standing ovarian cancer and fallopian tube tissue bank that is directed by Dr. Elizabeth Swisher will be utilized in this project. The proposal is innovative because the hypothesis is completely novel and has not been tested before even though it is biologically plausible and supported by previous studies. The proposed research is significant because by collecting direct evidence that associates ovarian cancer to an altered tubal microbiome, it is expected to vertically advance and expand our understanding of the pathogenesis of ovarian cancer and the pathological roles of fallopian tubes. Ultimately, such knowledge has the potential to decrease ovarian cancer mortality through early detection, prevention, or targeted therapy. During the career development award period, the applicant will have ample opportunities of interdisciplinary training in translational research, microbiology, genomics, and cancer biology, which will open a pathway to a productive research career and ultimately to a career goal of improving women’s health through scientific discoveries.