Immunological, epigenetic and developmental determinants of early pregnancy success

在美国，大约12%的女性生育力受损，7%的夫妇有不孕不育，其中三分之一可归因于 女性因素。然而，潜在的机制在很大程度上仍不清楚，即使在更近的情况下 病理被识别，因此排除了准确的诊断和个性化治疗的发展。 此外，不孕不育妇女的怀孕，无论是自然受孕还是不孕治疗的结果，都有 更高的并发症风险，如先兆子痫、早产和胎儿生长受限，这些都会导致终生 对后代的影响。因此，剖析生殖成功和妥协背后的机制 基因组、分子和细胞水平对今世后代的健康和福祉至关重要。 从多个学科聘请调查人员，并建立可持续的初级调查人员渠道， 包括那些在科学和医学方面代表性不足的人，对于这一努力也是至关重要的，促进 提高公众对生殖健康和科学的认识。这些是我们的NIH国家研究中心的核心原则 加州大学旧金山分校生殖与不孕症的转化性研究 (加州大学旧金山分校)，自2007年以来得到资助，这项新提案是为其提交的，重点是新的中心主题 围绝经期子宫内膜炎症、表观遗传学和发育过程的相互关系 着床、子宫和早期妊娠作为早期妊娠成败的核心决定因素。这 关注的动机是这样一个事实，即病理性子宫内膜炎和 女性不孕不育，虽然根深蒂固，但缺乏深刻的机械理解。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，由一个 行政核心(A)和教育/外联核心(B)。项目1(Roan/Huddleston，共同领导)重点 正常人和炎症性子宫内膜中淋巴细胞表型和功能的研究 和蜕膜，包括T和B细胞抗原特异性的测定。项目2(Erlebacher)专注于 子宫内膜和蜕膜基质细胞中活跃的表观遗传过程是如何控制的，进而又是如何控制的 由子宫内膜和蜕膜炎症引起。最后，项目3(Blelloch/Fisher，共同领导)解决了如何 构成母胎界面胎儿部分的胚胎外组织的原始滋养层细胞 区分决定着植入的胚胎相对于蜕膜的极性的亚型。 我们相信，我们的中心还将通过建立一个 在共享使用稀有临床标本的基础上成功开展跨学科合作的范例 通过互补性、多组学方法结合机械性调查进行分析 模型系统。我们的中心还旨在吸引学生、研究员和初级科学家到 生殖和不孕不育研究，并让社区参与不孕不育的重要性 研究。

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.