Immunological, epigenetic and developmental determinants of early pregnancy success

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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.