The role of fallopian tube microbiome in ovarian carcinogenesis

输卵管微生物组在卵巢癌发生中的作用

• 批准号: 10663005
• 负责人: Bo Yu
• 金额: $ 25.32万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10663005
• 关键词: 16S ribosomal RNA sequencing; Age; BRCA1 Mutation; Bacteria; Bilateral; Cancer Biology; Cancer Burden; Cancer-Predisposing Gene; DNA Damage; Diagnosis; Early Diagnosis; Epithelial Cells; Event; Female Genital Diseases; Future; Genomics; Goals; Histology; Infection; Inflammation; Inherited; Investigation; K-Series Research Career Programs; Knowledge; Legal patent; Life; Ligation; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Oviducts; Microbiology; Mission; Mutation; Oral Contraceptives; Ovarian; Ovarian Carcinoma; Pathogenesis; Pathologic; Pathway interactions; Patients; Prevention; Prevention strategy; Prevention therapy; Productivity; Public Health; Research; Risk; Role; Technology; Testing; Tissue Banks; Training; Translational Research; Tubal Ligation; Tube; United States National Institutes of Health; Woman; Women' s Health; carcinogenesis; career; cell injury; endometriosis; improved; innovation; microbiome; mortality; novel; premalignant; protective effect; reproductive tract; targeted treatment; transcriptome; treatment strategy

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.

项目概要/摘要 对卵巢癌的发病机制的理解存在根本性的差距。 已证实卵巢癌易感基因遗传突变，但大多数病例的直接原因尚不清楚。 对始发事件缺乏了解阻碍了早期发现、预防甚至预防的努力 这种最致命的妇科恶性肿瘤的靶向治疗该应用的总体目标是 研究导致卵巢癌的新途径，从而使未来的研究能够发展 卵巢癌发生的一个新颖但高度可信的中心假设。 这里提出：一些生殖道细菌的上行感染会导致输卵管炎症 多种证据支持这一假设，例如导致卵巢癌的细胞 DNA 损伤。 双侧输卵管结扎和口服避孕药对卵巢癌的保护作用 子宫内膜异位症与卵巢癌的风险增加然而，缺乏直接证据。 因此，该假设将通过追求四个具体目标来检验：1）确定微生物组是否 正常输卵管与根据具体情况诊断为卵巢癌的患者不同 2) 确定子宫内膜异位症患者的输卵管微生物群是否与正常人不同 无子宫内膜异位症的女性；3) 比较 BRCA1 突变患者的输卵管微生物组 无癌症患者与有癌前改变的患者；4) 比较以下患者的转录组： 结扎输卵管伞端的正常输卵管上皮细胞与年龄未通畅的输卵管伞端的输卵管上皮细胞 David Fredricks 博士完善的 16S rRNA 基因测序技术。 实验室，以及由 Elizabeth Swisher 博士领导的长期存在的卵巢癌和输卵管组织库 该提案具有创新性，因为该假设是完全新颖的并且具有创新性。 尽管它在生物学上是合理的并且得到了先前研究的支持，但之前尚未经过测试。 研究意义重大，因为通过收集卵巢癌与输卵管相关的直接证据 微生物组，有望垂直推进和扩大我们对卵巢发病机制的理解 最终，此类知识有可能减少。 在职业发展过程中通过早期发现、预防或靶向治疗降低卵巢癌死亡率。 奖励期间，申请人将有充足的机会接受转化研究的跨学科培训， 微生物学、基因组学和癌症生物学，这将为富有成效的研究事业和 最终实现通过科学发现改善女性健康的职业目标。

项目成果

The developmental competence of human metaphase I oocytes with delayed maturation in vitro.

人中期 I 卵母细胞体外延迟成熟的发育能力。

• 发表时间: 2023-04
• 影响因子: 6.7
• 作者: Moon, Jeong Hee;Zhao, Qianying;Zhang, Jiaqi;Reddy, Vik;Han, Jinnou;Cheng, Yuan;Zhang, Nan;Dasig, Jennifer;Nel;Behr, Barry;Yu, Bo
• 通讯作者: Yu, Bo