Periodic Reporting for period 1 - OOCSOCS (Socs3 gene in oocyte maturation and fertilisation - a novel link between inflammation and infertility)
Reporting period: 2017-06-01 to 2019-05-31
Reproductive aging and problematic female fertility are linked to increased inflammatory signalling. We initially focused on a previously identified candidate gene involved in the regulation of the inflammatory response, as well as placenta development, Suppressor of cytokine signalling 3 (Socs3). However, our research led us towards a much more fundamental role of the mTOR intra-cellular signalling pathway, also associated with inflammation and aging. Specifically, we studied the process of mTOR-regulated cap-dependent translation (a specialized and highly regulated form of cellular protein synthesis) and its effect on the oocyte maturation and the preimplantation embryonic development stages. We uncovered a novel fundamental effect of mTOR signalling on the spatial positioning of cells in the early embryo. Such spatial positioning is tightly associated with the segregation of individual and functional specialization of distinct cell lineages in the early embryo and mTOR signalling regulates the number of the progenitor cells that will give rise to the embryo itself (found encapsulated inside the developing embryonic mass), as oppose to outer-residing cells that ultimately form extraembryonic tissue (i.e. placenta). We also developed a highly optimised low input protocol for genome-wide profiling of actively translated mRNAs (molecular intermediates between genes and synthesis of the proteins they encode), applied it to maturing mouse oocytes and identified important differences in those from aged versus young females; with potential consequences for fertility. In addition, we studied the novel interplay of the mTOR and p38-mitogen-activated-kinase pathways in translation regulation at the late blastocyst stage (i.e. prior to uterine implantation), affecting the specification of the primitive endoderm extraembryonic cell lineage (needed to support the post-implantation developmental stages).
As a direct consequence of this award and the above summarised experiments progression, this project has also substantially contributed to the career progression of the postdoctoral researcher, Dr. Gahurova, towards becoming an independent group leader at the University of South Bohemia in Czech Republic.
The results of this project were published in 6 peer reviewed publications. One manuscript, constituting the main theme of the project, is at the advanced stage of preparation and is expected to be submitted to a peer-reviewed journal by the end of 2021. Furthermore, the results were presented at three international conferences (1 oral and two poster presentations), one invited oral presentation at an international conference (after finishing the project), and two seminars at the local academic institutions. In addition, the results were disseminated at 4 public engagement activities (for secondary school teachers, students, and primary school children). All this was achieved with two maternity breaks and Covid-19 pandemics lockdown (with attendant closed child day care).