Immunological, epigenetic and developmental determinants of early pregnancy success

早期妊娠成功的免疫学、表观遗传学和发育决定因素

• 批准号: 10673393
• 负责人: Adrian Erlebacher
• 金额: $ 165万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 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/10673393
• 关键词: Address; Affect; Age; Antigens; B-Lymphocytes; Basic Science; Biological Models; California; Cells; Center for Translational Science Activities; Chorion; Chorionic Sac; Clinical; Clinical Medicine; Communities; Conceptus; Couples; Decidua; Development; Developmental Process; Diagnostic; Discipline; Disease; Education; Education and Outreach; Endometrial; Endometrium; Environment; Epigenetic Process; Failure; Female; Female infertility; Fertility; Fetal Growth Retardation; Fetal Membranes; Fostering; Funding; Future Generations; Genomics; Goals; Health; Human; Immunologics; Impairment; Implant; Infertility; Inflammation; Inflammation Mediators; Inflammation Process; Inflammatory; Institution; Investigation; Lymphocyte; Marital Status; Maternal-Fetal Exchange; Medicine; Mentors; Mentorship; Molecular; Morbidity - disease rate; Outcome; Pathologic; Pathology; Personal Satisfaction; Phenotype; Pilot Projects; Placenta; Placenta Diseases; Polycystic Ovary Syndrome; Positioning Attribute; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Pregnant Women; Premature Birth; Process; Quality of life; Reproduction; Reproductive Health; Reproductive Medicine; Reproductive Sciences; Research; Research Personnel; Research Project Grants; Risk; Role; San Francisco; Science; Scientist; Specificity; Specimen; Stromal Cells; Students; Subfecundity; T-Lymphocyte; Technology; Time; Training; Translational Research; United States National Institutes of Health; Universities; Uterus; Villous; Woman; Work; World Health Organization; accurate diagnostics; adverse pregnancy outcome; aged; career; clinically relevant; community engagement; design; diversity and inclusion; early pregnancy; early pregnancy loss; embryo tissue; endometriosis; experience; fetal; health science research; implantation; infertility treatment; innovation; insight; interdisciplinary collaboration; literacy; member; multiple omics; novel; offspring; outreach; personalized medicine; preimplantation; reproductive; reproductive outcome; reproductive success; subfertility; success; targeted treatment; translational approach; trophoblast

In the U.S., about 12% of women have impaired fecundity and 7% of couples have infertility, with 1/3 attributable to female factors. Underlying mechanisms remain largely unknown, however, even when more proximal pathologies are identified, thus precluding the development of accurate diagnostics and personalized therapies. In addition, pregnancies in subfertile women, conceived naturally or as a result of infertility treatments, have greater risk of complications such as pre-eclampsia, preterm birth, and fetal growth restriction that have life-long effects on the offspring. Thus, dissecting the mechanisms underlying reproductive success and compromise at the genomic, molecular, and cellular level is crucial to the health and well-being of this and future generations. Engaging investigators from multiple disciplines and building a sustainable pipeline of junior investigators, including those underrepresented in science and medicine, is also essential to this effort, as is the promotion of public literacy about reproductive health and science. These are core principles of our NIH National Center for Translational Research in Reproduction and Infertility (NCTRI) at the University of California San Francisco (UCSF), funded since 2007 and for which this new proposal is submitted with a new central theme focused on the inter-related roles of endometrial inflammation, epigenetics, and developmental processes of the peri- implantation uterus and early conceptus as central determinants of early pregnancy success or failure. This focus is motivated by the fact that the clinical association between pathological endometrial inflammation and female infertility, while well-established, lacks a deep mechanistic understanding. Our proposed Center is comprised of three inter-related Research Projects and a pilot project (to be determined), supported by an administrative core (A), and an education/outreach core (B). Project 1 (Roan/Huddleston, co-Leads) focuses on the phenotypes and functions of endometrial lymphocytes in the normal and inflamed human endometrium and decidua, including determinations of T and B cell antigen specificities. Project 2 (Erlebacher) focuses on how epigenetic processes active within endometrial and decidual stromal cells control, and are in turn controlled by, endometrial and decidual inflammation. Lastly, Project 3 (Blelloch/Fisher, co-Leads) addresses how primitive trophoblasts of the extra-embryonic tissues that comprise the fetal portion of maternal-fetal interface differentiate into the subtypes that determine the polarity of the implanted conceptus with respect to the decidua. We believe our Center will also advance reproduction and infertility research more generally by setting an example of successful transdisciplinary collaboration built upon the shared use of rare clinical specimens analyzed through complementary, multi-omics approaches combined with mechanistic investigations using model systems. Our Center also is designed to attract students, fellows, and junior scientists to careers in reproduction and infertility research, and to engage the community with regards to the importance of infertility research.

在美国，大约 12% 的女性生育能力受损，7% 的夫妇患有不孕症，其中 1/3 归因于 到女性因素。然而，即使更接近，潜在的机制仍然很大程度上未知。 病理学被识别，从而阻碍了准确诊断和个性化治疗的发展。 此外，生育力低下的女性，无论是自然受孕还是因不孕治疗而怀孕， 发生先兆子痫、早产和胎儿生长受限等终生并发症的风险更大 对后代的影响。因此，剖析生殖成功和妥协的潜在机制 基因组、分子和细胞水平对于这一代人和子孙后代的健康和福祉至关重要。 吸引来自多个学科的研究人员并建立可持续的初级研究人员渠道， 包括那些在科学和医学领域代表性不足的人，对于这项努力也至关重要，就像促进 公众对生殖健康和科学的认识。这些是我们 NIH 国家中心的核心原则 加州大学旧金山分校生殖与不孕症转化研究 (NCTRI) （UCSF），自 2007 年起获得资助，为此提交的新提案的新中心主题侧重于 子宫内膜炎症、表观遗传学和围周发育过程的相互关联的作用 着床子宫和早期受孕是早期妊娠成功或失败的核心决定因素。这 病理性子宫内膜炎症与子宫内膜异位症之间的临床关联这一事实激发了人们的关注。 女性不孕症虽然已得到证实，但缺乏深入的机制认识。我们建议的中心是 由三个相互关联的研究项目和一个试点项目（待定）组成，并得到 行政核心（A）和教育/外展核心（B）。项目 1（Roan/Huddleston，联合负责人）重点 正常和发炎的人类子宫内膜中子宫内膜淋巴细胞的表型和功能 和蜕膜，包括 T 和 B 细胞抗原特异性的测定。项目 2 (Erlebacher) 重点关注 表观遗传过程如何在子宫内膜和蜕膜基质细胞中活跃，并反过来被控制 由子宫内膜和蜕膜炎症引起。最后，项目 3（Blelloch/Fisher，共同负责人）解决了如何 胚胎外组织的原始滋养层，构成母胎界面的胎儿部分 分化为决定植入的概念相对于蜕膜的极性的亚型。 我们相信，我们的中心还将通过设立一个 基于共享使用稀有临床标本的成功跨学科合作的例子 通过互补的多组学方法结合机械研究进行分析 模型系统。我们中心还旨在吸引学生、研究员和初级科学家从事以下领域的职业 生殖和不孕不育研究，并让社区了解不孕不育的重要性 研究。