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

女性和男性生殖微环境在生育健康中的作用

• 批准号: 10555717
• 负责人: Douglas Brubaker
• 金额: $ 55.57万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555717
• 关键词: Address; Antigen-Presenting Cells; Assisted Reproductive Technology; Biological Assay; Biopsy; CCL2 gene; Cells; Cervical; Chromosome abnormality; Clinical; Computer Analysis; Coupled; Couples; DNA; DNA Damage; Data; Diagnosis; Ecology; Embryo; Embryo Transfer; Emotional; Endometrial; Enrollment; Environment; Female; Female genitalia; Female infertility; Fertility; Fertilization in Vitro; Flow Cytometry; Gene Expression Profile; Genetic Screening; Genitourinary system; Hormonal; Human Chorionic Gonadotropin; IL7 gene; IL8 gene; Immune; Immunology; Individual; Infertility; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-1 beta; Interleukin-10; Interleukin-6; Knowledge; Live Birth; Machine Learning; Male Genital Organs; Male Infertility; Men' s Role; Modeling; Morphology; Mucous Membrane; Oocytes; Outcome; Participant; Pregnancy; Pregnancy Rate; Procedures; Process; Production; Recording of previous events; Reproductive Health; Research; Research Personnel; Sampling; Seminal; Seminal fluid; Specimen; Sperm Count Procedure; Swab; System; Systems Biology; TNF gene; Techniques; Testing; Therapeutic; Time; Training; Tryptophan; Unsafe Sex; Uterus; Vagina; Volatile Fatty Acids; Women' s Role; cell motility; cervicovaginal; cohort; conditioning; cost; cytokine; dysbiosis; failure Implantation; female fertility; fitness; high dimensionality; host-microbe interactions; implantation; improved; male; male fertility; metabolomics; metaproteomics; microbial; microbiome; microbiome composition; natural Blastocyst Implantation; new therapeutic target; novel therapeutic intervention; penis; post pregnancy; predictive modeling; reproductive; single-cell RNA sequencing; sperm quality; success; tumor-immune system interactions; ultrasound; urogenital tract

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.

八分之一的夫妇受到不孕症的影响，不孕症的定义是难以获得或维持怀孕 经过一年的无保护性交，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基因筛查， 40%的胚胎移植仍然不成功。缺乏全面的粘膜系统水平数据， 描述的植入以及IVF背景下的女性和男性生育力终点限制了我们的研究。 了解可能导致不育的潜在微生物组、免疫和伴侣间相互作用 和治疗成功，这限制了治疗选择。因此，鉴定宿主-微生物相互作用 在女性和男性伴侣中，不孕症潜在夫妇内特征可能导致新的治疗方法， 目标或预测模型，以提高临床妊娠率，这将是一个重大的进步。 我们的总体假设是，泌尿生殖道微生物组的生态失调和功能驱动宿主 导致女性和男性因素不育的炎症过程。在本提案中，我们将 研究男性和女性不育症的微生物组和免疫驱动因素， 明确定义的不孕症和妊娠终点，以表征子宫内膜、宫颈阴道、精液和 阴茎因素有助于IVF成功。我们将收集子宫内膜和宫颈阴道样本， 女性伴侣在子宫内膜容受性测定（ERA）周期期间，该周期模拟激素条件 在随后的胚胎移植周期中出现。该队列的一个独特特征是有针对性地招募 有女性或男性生育问题的夫妇，提供评估生育相互作用的能力， 情侣级别。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 利用计算分析、单细胞RNA测序、元蛋白质组学、代谢组学和宿主细胞 分析加上先进的多变量建模技术，以确定女性的影响， 男性生殖器微环境对生育力的影响，具有女性，男性，以及内部和内部的特征。 导致生育能力下降的夫妇特征在这项提案中，我们的目标是确定女性的影响， 生殖器微环境（炎症和微生物组）对着床成功的影响， 微环境对精液质量和男性因素不育的影响，并描述夫妇间的特征 女性和男性伴侣的微环境之间的差异，导致了生育能力的下降。 这些研究将确定与不育相关的宿主和微生物因素，并有助于了解两者 个人内部和伙伴间的相互作用，可能有助于生育结果，这可以确定新的 治疗策略或预测模型，以提高临床妊娠率。