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，约12%的妇女生育能力受损，7%的夫妇患有不孕症，1/3的人可归因于 女性因素。然而，即使在更近端的情况下， 病理被识别，从而妨碍了准确诊断和个性化治疗的发展。 此外，自然受孕或不孕症治疗后受孕的低生育力妇女， 更大的并发症风险，如先兆子痫、早产和胎儿生长受限， 对后代的影响。因此，解剖生殖成功和妥协的潜在机制， 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。 让来自多个学科的调查员参与进来，并建立一个可持续的初级调查员管道， 包括那些在科学和医学领域代表性不足的人，对这一努力也至关重要， 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， 加州旧金山弗朗西斯科生殖与不孕症转化研究 （加州大学旧金山分校），自2007年以来资助，这一新的建议是提交了一个新的中心主题，重点是 子宫内膜炎症、表观遗传学和子宫内膜发育过程的相互作用， 着床子宫和早期妊娠是早期妊娠成功或失败的中心决定因素。这 关注的动机是病理性子宫内膜炎症和 女性不孕症虽然已得到公认，但缺乏深刻的机理理解。我们提议的中心是 包括三个相互关联的研究项目和一个试点项目（待定），由 行政核心（A）和教育/外展核心（B）。项目1（Roan/Huddfeld，共同牵头人）侧重于 对正常和炎症子宫内膜淋巴细胞表型和功能的影响 和蜕膜，包括T和B细胞抗原特异性的测定。项目2（Erlebacher）侧重于 子宫内膜和蜕膜间质细胞内的表观遗传过程是如何控制和反过来控制的 子宫内膜和蜕膜炎症。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，包括母胎界面的胎儿部分 分化成决定植入的孕体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 基于共享使用罕见临床标本而建立的成功跨学科合作范例 通过互补的多组学方法与使用 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从事以下职业 生殖和不育研究，并让社区了解不育的重要性 research.