Uterine microbiome: Functional significance in establishing the uterine program postpartum

子宫微生物组：在建立产后子宫计划中的功能意义

• 批准号: 9762958
• 负责人: Matthew C Lucy
• 金额: $ 32.16万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9762958
• 关键词: Address; Affect; Animals; Antibiotic Therapy; Antimicrobial Resistance; Area; Breeding; Cattle; Cattle Diseases; Cervix Uteri; Cessation of life; Chronic; Cicatrix; DNA Methylation; Data; Development; Diagnosis; Disease; Endometritis; Endometrium; Environment; Epigenetic Process; Failure; Fertility; Fibrosis; Functional disorder; Funding Opportunities; Gene Expression; Goals; Habitual Abortion; Human; Immune response; Infection; Infectious Agent; Infertility; Inflammation; Inflammatory; Investigation; Knowledge; Lead; Left; Metagenomics; Microbiology; Modeling; National Institute of Child Health and Human Development; Natural regeneration; Organ; Organism; Outcome; Pathogenicity; Pathology; Pattern; Pelvic Inflammatory Disease; Physiology; Postpartum Period; Postpartum Programs; Pregnancy; Pregnant Uterus; Process; Reproduction; Research; Risk; Specialist; Structure; Systems Biology; Tissues; United States; Uterine Diseases; Uterus; Vagina; Veterinarians; Woman; Work; agricultural community; bisulfite sequencing; experience; immune function; innovation; laser capture microdissection; metabolome; metagenomic sequencing; microbiome; microorganism; novel; pregnant; prevent; programs; reproductive; reproductive tract; subfertility; tissue regeneration; tissue repair; tool; transcriptome; transcriptome sequencing; transcriptomics; uterine receptivity; whole genome

PROJECT SUMMARY Approximately one-third of postpartum cows develop uterine disease (metritis) within one week after calving and 5% of all calvings result in death of the cow within 30 days due to metritis or other complications that originate during calving. Postpartum uterine infection in women is less common, but approximately 10% of pregnancy-related deaths in the United States are caused by puerperal genital tract infection. Cows with early postpartum uterine disease will develop chronic inflammation of the uterus (endometritis or subclinical endometritis; SCE). Chronic endometritis in women (pelvic inflammatory disease; PID) is similar to the bovine disease and is caused by a variety of bacterial species. If left untreated, both SCE and PID cause infertility. The inability to effectively treat uterine disease and restore fertility may be partially explained by a critical gap in understanding of the uterine microbiome and its relationship to the disease status, uterine immune function, inflammation, tissue regeneration, and long-term programming of uterine dysfunction. The goal of this proposal is to understand the origins of uterine disease and the mechanisms through which uterine disease programs subfertility and infertility. The studies begin with the virgin bovine uterus where the presence and viability of the microbiome after first breeding will be determined (Aim 1; Study 1A & 1B). The microbiome of first and second pregnancy will then be studied (Aim 1, Study 1C). Whether metritis during the early postpartum period permanently damages the endometrium through structural and functional mechanisms and whether systemic antibiotic treatment mitigates the effect is the subject of Aim 2. Finally, the embryotrophic capacity of the diseased endometrium will be assessed (Aim 3). Collectively, the proposed investigations will elucidate novel structural and functional mechanisms through which the microbiome programs fertility. The research is innovative from both a conceptual and technical perspective. The uterine microbiome and its effect on fertility is an exciting new area of research and conceptually innovative. The cow provides an innovative model for uterine disease research due to the remarkable similarity between uterine disease states and outcomes in cows and women. Whole genome metagenomic sequencing will be performed as this approach will enable us to assess the entire microbiome. The transcriptome will be studied by using laser capture microdissection (LCM) and RNA sequencing. Reduced representation bisulfite sequencing (RRBS) will be used to identify patterns of DNA methylation associated with changes in the transcriptome. The proposed studies will identify tissue-specific mechanisms through which the endometrium fails to establish a receptive uterine environment and the cow fails to become pregnant. This fundamental knowledge is necessary to develop innovative tools to diagnose, treat, and ameliorate the effects of uterine disease. If disease mechanisms are understood then it may be possible to prevent tissue damage and (or) reverse the programming to fully restore fertility in women and or cattle that experience uterine disease.

项目概要 大约三分之一的产后奶牛在产犊后一周内出现子宫疾病（子宫炎） 5% 的产犊会导致奶牛在 30 天内因子宫炎或其他并发症而死亡 起源于产犊期间。女性产后子宫感染不太常见，但大约有 10% 在美国，与妊娠相关的死亡是由产后生殖道感染引起的。奶牛早 产后子宫疾病会发展为子宫慢性炎症（子宫内膜炎或亚临床子宫炎） 子宫内膜炎; SCE）。女性慢性子宫内膜炎（盆腔炎；PID）与牛的慢性子宫内膜炎相似 疾病，是由多种细菌引起的。如果不及时治疗，SCE 和 PID 都会导致不孕。 无法有效治疗子宫疾病和恢复生育能力的部分原因可能是存在重大差距 了解子宫微生物组及其与疾病状态、子宫免疫功能的关系， 炎症、组织再生和子宫功能障碍的长期规划。此举的目标 该提案旨在了解子宫疾病的起源以及子宫疾病发生的机制。 计划生育力低下和不孕不育。研究从处女牛子宫开始，那里存在和 将确定首次育种后微生物组的活力（目标 1；研究 1A 和 1B）。微生物组 然后将研究第一次和第二次怀孕（目标 1，研究 1C）。早期是否有子宫炎 产后期通过结构和功能机制永久性地损害子宫内膜， 全身抗生素治疗是否会减轻影响是目标 2 的主题。最后，胚胎营养 将评估患病子宫内膜的容量（目标 3）。总的来说，拟议的调查将 阐明微生物组控制生育力的新结构和功能机制。这 研究无论从概念还是技术角度都具有创新性。子宫微生物组及其影响 关于生育力的研究是一个令人兴奋的新研究领域，并且在概念上具有创新性。牛提供了一种创新 由于子宫疾病状态和子宫疾病之间的显着相似性，子宫疾病研究模型 对奶牛和妇女的结果。全基因组宏基因组测序将按照这种方法进行 将使我们能够评估整个微生物组。将使用激光捕获来研究转录组 显微切割 (LCM) 和 RNA 测序。简化代表性亚硫酸氢盐测序（RRBS）将 用于识别与转录组变化相关的 DNA 甲基化模式。拟议的 研究将确定子宫内膜无法建立接受性的组织特异性机制 子宫环境不好，母牛无法怀孕。这些基础知识对于 开发创新工具来诊断、治疗和改善子宫疾病的影响。如果有疾病 了解机制后，就有可能防止组织损伤和（或）逆转组织损伤 旨在完全恢复患有子宫疾病的妇女和/或牛的生育能力的计划。