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

项目总结 女性生殖道的细菌感染在妇女和奶牛中都很常见。这些子宫 感染会导致这两个物种的不孕，但导致受孕失败的具体机制仍然存在。 不清楚。新出现的证据表明，感染会影响卵巢健康，而卵巢问题 不孕症的重要原因与子宫感染有关。病原体相关分子启动 子宫感染奶牛卵泡液中炎症反应集中，卵巢功能受损 紊乱导致黄体期延长，性激素分泌减少，局部炎症反应 并降低卵母细胞的质量。此外，牛卵巢外植体或小鼠暴露于与病原体相关的 分子加速了原始卵泡储备的激活，表明感染可能会耗尽总的 卵巢中可用卵泡的数量会降低整体的长期生育力。在女性中，盆腔炎 这种疾病是由生殖道细菌感染常见的性传播病原体引起的。 不孕症患者中有10%患有不孕症，卵巢病理是这种疾病的一个组成部分，包括卵巢衰竭。 卵泡储备量。此外，更高比例的试管受精患者患有子宫感染，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 卵巢反应差，妊娠率低。 我们假设病原体相关分子和卵巢卵泡炎性反应 这些分子会损害卵母细胞的健康，耗尽卵巢的卵泡储备。这个项目将 利用子宫感染动物模型研究奶牛卵巢功能障碍的机制。目标1 将侧重于感染对卵母细胞本身的影响，而目标2将侧重于子宫感染对卵子本身的影响 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 卵泡处于适当的活体系统中。同时，我们将利用体外细胞和分子技术 目的：确定感染导致卵巢功能障碍的机制。总而言之，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药物限制子宫的影响提供靶向的作用机制。 疾病对卵巢健康的影响。通过了解卵巢功能障碍的这些机制，我们可以帮助保护 生育，或最大限度地减少感染对卵巢的影响，通过使用免疫的药物操作 感染介导性不孕症的系统和信号通路。这些研究对美国国立卫生研究院的益处 而美国农业部将提高妇女和奶牛的健康和繁殖力，从而产生更积极的影响 提高妇女的妊娠结局，改善农业安全和奶制品行业的盈利能力。

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.