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

项目摘要 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 感染导致两种物种的不育，但导致怀孕失败的具体机制仍然存在。 不清楚新出现的证据表明，感染影响卵巢健康，卵巢问题是 不孕症的重要原因与子宫感染有关。病原体相关分子启动 炎症都集中在卵泡液奶牛子宫感染和卵巢功能是 破坏导致黄体期延长，性激素产生减少，局部炎症反应 和降低的卵母细胞质量。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总的 卵巢中可用的卵泡数量，并降低整体长期生育能力。女性盆腔炎 这种疾病是由于生殖道受到常见性传播病原体的细菌感染所致。 不孕症影响10%的PID患者，卵巢病理是这种疾病的一个组成部分，包括消耗 卵泡储备。此外，更高比例的试管婴儿患者患有子宫感染， 生殖道衣原体抗体滴度或病原体相关分子升高的患者， 卵巢反应性差，妊娠率低。 我们假设病原体相关分子和卵巢卵泡炎症反应， 这些分子会损害卵母细胞的健康并消耗卵巢卵泡储备。该项目将 利用子宫感染动物模型研究奶牛卵巢功能障碍的机制。要求1 Aim 2将关注感染对卵母细胞本身的影响，而Aim 2将关注子宫感染对卵母细胞的影响。 卵泡动力学这些研究将使我们能够确定感染对卵母细胞的影响， 在适当的体内系统中的卵巢卵泡。同时，我们将利用体外细胞和分子技术 以确定感染导致卵巢功能障碍的机制。综合考虑，我们预计 寻找病原体相关分子和炎症与免疫功能障碍之间的共同机制， 卵母细胞和卵泡。 这些发现将为使用治疗剂限制子宫内膜异位症的影响提供靶向作用机制。 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 生育能力，或尽量减少感染对卵巢的影响，通过使用免疫药理学操作， 系统和信号通路参与感染介导的不育。这些研究对国家卫生研究院的益处 美国农业部将提高妇女和奶牛的健康和繁殖力， 妇女的妊娠结局以及改善农业安全和乳品业的盈利能力。

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.