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: 10355543
• 负责人: Bo Yu
• 金额: $ 16.77万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10355543
• 关键词: 16S ribosomal RNA sequencing; Age; BRCA1 Mutation; BRCA1 gene; BRCA2 gene; Bacteria; Bacterial Infections; Bilateral; Biology; Cancer Biology; Cancer Burden; Cancer-Predisposing Gene; Cessation of life; Clear Cell; Communication; DNA Damage; Development; Diagnosis; Disease; Down-Regulation; Early Diagnosis; Environment; Epithelial; Epithelial Cells; Event; Female Genital Diseases; Future; Genomics; Goals; Gonadotropins; Grant; Greater sac of peritoneum; Histologic; Histology; Hysterectomy; Incidence; Infection; Inflammation; Inflammatory; Inherited; Integration Host Factors; Investigation; K-Series Research Career Programs; Knowledge; Lead; Legal patent; Lesion; Life; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Oviducts; Mediating; Mentors; Microbiology; Mission; Mutation; Neoplasms; Operative Surgical Procedures; Oral Contraceptives; Outcome; Ovarian; Ovarian Carcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Serous Adenocarcinoma; Ovarian Tissue; Ovulation; Pathogenesis; Pathologic; Pathway interactions; Patients; Pelvic Inflammatory Disease; Powder dose form; Prevention; Prevention strategy; Prevention therapy; Public Health; Research; Risk; Risk Reduction; Role; Site; Surface; Survival Rate; TP53 gene; Talc; Taxonomy; Technology; Testing; Tissue Banks; Tissues; Training; Translational Research; Tubal Ligation; Tube; United States; United States National Institutes of Health; Vagina; Woman; Women' s Health; base; cancer risk; carcinogenesis; career; cell injury; endometriosis; epidemiology study; improved; inflammatory milieu; innovation; microbial; microbiome; mortality; novel; pathogen; premalignant; protective effect; reproductive tract; targeted treatment; theories; 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 对卵巢癌发病机制的理解存在根本性差距。以外 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。该应用程序的总体目标是 研究导致卵巢癌的新途径，从而使未来的研究能够发展 预防和治疗策略。卵巢癌发生的一个新颖但高度合理的中心假说 这里提出：一些生殖道细菌的上行感染会导致输卵管炎症 输卵管和细胞 DNA 损伤导致卵巢癌。多项证据支持这一点 假设，例如双侧输卵管结扎和口服避孕药对卵巢的保护作用 癌症，以及与子宫内膜异位症相关的卵巢癌风险增加。然而，直接证据是 缺乏。因此，该假设将通过追求四个具体目标来检验：1）确定是否 正常输卵管的微生物组与卵巢癌诊断患者的微生物组不同 特定的组织学； 2) 确定子宫内膜异位症患者的输卵管微生物群是否不同 与没有子宫内膜异位症的女性相比； 3) 比较不同类型患者的输卵管微生物组 BRCA1 突变者未患癌症，且患有癌前改变； 4）比较 来自结扎管伞端的正常输卵管上皮细胞的转录组与来自结扎管的伞端的转录组 年龄匹配对照中的专利管。国内成熟的16S rRNA基因测序技术 David Fredricks 博士的实验室，以及一个长期存在的卵巢癌和输卵管组织库，由 Elizabeth Swisher 博士将参与该项目。该提议具有创新性，因为假设是 完全新颖，之前从未经过测试，尽管它在生物学上是合理的并且得到了支持 以前的研究。拟议的研究意义重大，因为通过收集直接证据表明 卵巢癌改变了输卵管微生物组，预计它会垂直推进和扩大我们的 了解卵巢癌的发病机制和输卵管的病理作用。最终， 这些知识有可能通过早期发现、预防或降低卵巢癌死亡率 靶向治疗。在职业发展奖励期内，申请人将有充足的机会 转化研究、微生物学、基因组学和癌症生物学的跨学科培训即将开放 通往富有成效的研究生涯并最终实现改善妇女健康的职业目标的途径 科学发现。