Uterine infection and infertility: how microbial infection of the reproductive tract causes ovarian dysfunction.

子宫感染和不孕：生殖道微生物感染如何导致卵巢功能障碍。

• 批准号: 9149499
• 负责人: John J Bromfield
• 金额: $ 36.98万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9149499
• 关键词: Affect; Agriculture; Animal Model; Animals; Antibodies; Bacteria; Bacterial Infections; Cattle; Cells; Chlamydia; Clinical; Competence; Conceptions; Development; Disease; Distant; Embryo; Endocrine; Failure; Female; Fertility; Follicular Fluid; Functional disorder; Goals; Gonadal Steroid Hormones; Growth; Health; Hematopoietic; Human; Immune; Immune system; In Vitro; Industry; Infection; Infertility; Inflammation; Inflammation Mediators; Inflammatory Response; Intervention; Knowledge; Link; Luteal Phase; Mammals; Mammary gland; Mediating; Meiosis; Modeling; Molecular; Mus; Natural Immunity; Oocytes; Ovarian; Ovarian Follicle; Ovarian Tissue; Ovary; Ovulation; Pathology; Pathway interactions; Patients; Pelvic Inflammatory Disease; Pregnancy Outcome; Pregnancy Rate; Primordial Follicle; Production; Reproductive Tract Infections; Resolution; Security; Sexually Transmitted Diseases; Signal Pathway; Site; System; Techniques; Testing; Therapeutic Uses; Tissues; United States National Institutes of Health; Uterine Diseases; Uterus; Woman; Work; fertility improvement; granulosa cell; improved; in vivo; insight; microbial; pathogen; receptor; reproductive tract; response; success

Project summary Bacterial infections of the female reproductive tract are common in both women and dairy cows. These uterine infections cause infertility in both species, but the specific mechanisms resulting in a failure to conceive remains unclear. Emerging evidence suggest that the infection impacts ovarian health, and that ovarian problems are important causes of the infertility associated with uterine infection. Pathogen-associated molecules which initiate inflammation are concentrated in the follicular fluid of dairy cows with uterine infection and ovarian function is disrupted resulting in extended luteal phases, less sex hormone production, localized inflammatory responses and reduced oocyte quality. Furthermore, exposure of bovine ovarian explants or mice to pathogen-associated molecules accelerates activation of the primordial follicle reserve, suggesting that infection may deplete the total number of follicles available in the ovary and reduce overall long-term fertility. In women, pelvic inflammatory disease results from bacterial infection of the reproductive tract with common sexually transmitted pathogens. Infertility affects 10% of PID patients, and ovarian pathology is a component of this disease, including depletion of the follicle reserve. In addition, a higher proportion of IVF patients have suffered uterine infection, while patients with elevated Chlamydia antibody titers or pathogen-associated molecules in the reproductive tract have poor ovarian response and lower pregnancy rates. We hypothesize that pathogen-associated molecules, and ovarian follicle inflammatory responses to these molecules, compromises oocyte health and depletes the ovarian follicle reserve. This project will utilize an animal model of uterine infection to study the mechanisms of ovarian dysfunction in dairy cows. Aim 1 will focus on the impact of infection on the oocyte itself, while Aim 2 will focus on effects of uterine infection on ovarian follicle dynamics. These studies will allow us to determine the impact of infection on the oocyte and ovarian follicle in an appropriate in vivo system. In parallel we will utilize in vitro cellular and molecular techniques to determine the mechanisms by which infection results in ovarian dysfunction. Taken together we anticipate finding common mechanisms that link pathogen-associated molecules and inflammation with the dysfunction of oocytes and ovarian follicles. These discoveries will provide target mechanisms of action for using therapeutics to limit the impact of uterine disease on ovarian health. By understanding these mechanisms of ovarian dysfunction we can help protect fertility, or minimize the impact of infection on the ovary, by using pharmacological manipulations of the immune system and signaling pathways involved in infection-mediated infertility. The benefit of these studies to the NIH and USDA will be to increase the health and fecundity of women and dairy cows, resulting in more positive pregnancy outcomes in women and improving agricultural security and profitability for the dairy industry.

项目概要 女性生殖道的细菌感染在女性和奶牛中都很常见。这些子宫 感染会导致两个物种不孕，但导致无法受孕的具体机制仍然存在 不清楚。新的证据表明，感染会影响卵巢健康，而卵巢问题是 子宫感染是导致不孕的重要原因。启动病原体相关分子 子宫感染、卵巢功能低下的奶牛，炎症集中在卵泡液中 扰乱导致黄体期延长、性激素产生减少、局部炎症反应 并降低卵母细胞质量。此外，牛卵巢外植体或小鼠暴露于病原体相关的 分子加速了原始卵泡储备的激活，这表明感染可能会耗尽原始卵泡储备 卵巢中可用卵泡的数量并降低总体长期生育能力。对于女性来说，盆腔炎 该疾病是由常见性传播病原体生殖道细菌感染引起的。 10% 的 PID 患者患有不孕症，卵巢病理学是该疾病的一个组成部分，包括卵巢功能衰竭 的卵泡储备。此外，IVF患者中出现子宫感染的比例较高，而 生殖道中衣原体抗体滴度或病原体相关分子升高的患者 卵巢反应较差，妊娠率较低。 我们假设病原体相关分子和卵泡炎症反应 这些分子会损害卵母细胞的健康并耗尽卵泡储备。该项目将 利用子宫感染的动物模型来研究奶牛卵巢功能障碍的机制。目标1 目标 2 将重点关注感染对卵母细胞本身的影响，而目标 2 将重点关注子宫感染对卵母细胞本身的影响。 卵巢卵泡动力学。这些研究将使我们能够确定感染对卵母细胞和 卵泡位于适当的体内系统中。与此同时，我们将利用体外细胞和分子技术 确定感染导致卵巢功能障碍的机制。综合起来，我们预计 寻找将病原体相关分子和炎症与功能障碍联系起来的共同机制 卵母细胞和卵泡。 这些发现将为使用治疗方法限制子宫的影响提供目标作用机制。 卵巢健康的疾病。通过了解卵巢功能障碍的这些机制，我们可以帮助保护 通过使用免疫药物操作来降低生育能力，或最大程度地减少感染对卵巢的影响 感染介导的不孕症涉及的系统和信号通路。这些研究对 NIH 的好处 美国农业部将提高妇女和奶牛的健康和生育能力，从而产生更积极的结果 妇女怀孕结果以及改善农业安全和乳制品行业的盈利能力。