The role of the female and male reproductive microenvironment in fertility fitness

每八对夫妇中就有一对受到不孕不育的影响，不孕症的定义是难以获得或维持怀孕 在一年的无保护措施的性行为之后，许多夫妇转向昂贵的辅助生殖技术 例如体外受精(IVF)。即使对胚胎进行染色体异常的遗传筛查， 40%的胚胎移植仍然不成功。缺乏全面的粘膜系统水平的数据与井 在体外受精的背景下所描述的植入和女性和男性生育终点限制了我们的 了解可能导致不孕症的潜在微生物群、免疫和性伴侣内相互作用 治疗成功，治疗选择有限。因此，识别宿主-微生物的相互作用 在女性和男性伴侣中，以及潜在的不孕症夫妇内部签名可能导致新的治疗方法 提高临床妊娠率的目标或预测模型，这将是一个重大的进步。 我们的全球假设是，泌尿生殖系统微生物群的非生物生态和功能驱动宿主 导致女性和男性因素不孕的炎症过程。在本提案中，我们将 利用配对队列研究男性和女性不孕症的微生物群和免疫驱动因素 明确的不孕症和妊娠终点，以确定子宫内膜、宫颈阴道、精液和 阴茎因素导致试管受精成功。我们将收集子宫内膜和宫颈阴道样本 模拟激素状态的子宫内膜容受性测定(ERA)周期中的女性伴侣 出现在随后的胚胎移植周期中。这一群体的一个独特特点是有针对性地招收 有女性或男性生育问题的夫妇，提供了一次评估生育交互作用的能力 两个级别。我们将利用最先进的系统生物学方法，包括高维流式细胞术 通过计算分析、单细胞RNA测序、代谢组学和宿主细胞 分析结合先进的多变量建模技术来确定女性和 男性生殖器微环境对生育能力的影响，具有女性、男性以及内部和外部两个方面的特征 导致生育率下降的几个签名。在这项建议中，我们的目标是确定女性 生殖器微环境(炎症和微生物群)对植入成功、精液的影响 微环境对精液质量和男性不育因素的影响以及夫妻间特征的表征 女性和男性伴侣之间的微环境共同降低了生育率。 这些研究将确定与不孕症相关的宿主和微生物因素，并有助于了解两者 个人内部和伴侣之间的互动可能有助于生育结果，这可能会确定新的 提高临床妊娠率的治疗策略或预测模型。

One in eight couples are impacted by infertility, defined as difficulty obtaining or sustaining a pregnancy after one year of unprotected intercourse, and many couples turn to costly assisted reproductive technologies such as in vitro fertilization (IVF). Even with genetic screening of embryos for chromosomal abnormalities, up to 40% of embryo transfers are still unsuccessful. The lack of comprehensive mucosal systems-level data with well described implantation and both female and male fertility endpoints in the context of IVF has limited our understanding of potential microbiome, immune and intra-partner interactions that may contribute to infertility and treatment success, which has limited therapeutic options. Therefore, identifying host-microbial interactions in both female and male partners and potential intra-couple signatures of infertility could lead to novel therapeutic targets or predictive models to increase clinical pregnancy rates, which would be a significant advance. Our global hypothesis is that dysbiotic ecology and function of urogenital microbiomes drive host inflammatory processes that contribute to female and male factor infertility. In this proposal we will investigate the microbiome and immune drivers of male and female infertility by utilizing a partnered cohort with well-defined infertility and pregnancy endpoints to characterize the endometrial, cervicovaginal, seminal and penile factors contributing to IVF success. We will collect endometrial and cervicovaginal samples from the female partner during an endometrial receptivity assay (ERA) cycle which mimics the hormonal conditions present during subsequent embryo transfer cycles. A unique feature of this cohort is targeted enrollment of couples with either female or male fertility issues, providing the ability to assess fertility interactions at a per couple level. We will utilize a state-of-the-art systems biology approach including high dimensional flow cytometry with computational analysis, single cell RNA sequencing, metaproteomics, metabolomics, and host cellular analysis coupled with advanced multivariate modeling techniques to determine the effect of the female and male genital microenvironment on fertility, with the characterization female, male, and both intra- and inter- couple signatures that underlie decreased fertility. In this proposal we aim to determine the effect of the female genital microenvironment (inflammation and microbiome) on implantation success, the seminal microenvironment on semen quality and male factor infertility, and to characterize the inter-couple signatures between female and male partner microenvironment that underlie combined decreased fertility. These studies will identify host and microbial factors associated with infertility and help understand both intra-individual and inter-partner interactions that could contribute to fertility outcomes, which could identify novel therapeutic strategies or predictive models to increase clinical pregnancy rates.