Kliniken & Institute … Kliniken Frauenklinik (Zentrum) … Gynäkologische… Forschung AG Krivega

AG Krivega

The consequences of genetic abnormalities are detrimental for development of human embryo. Abnormal number of chromosomes, so-called aneuploidy, is associated with spontaneous abortion and the rare embryos surviving have problems with tissue specification often resulting in cancer. Our research is focused on understanding the mechanisms of cell specification in humans.

Previously I analyzed involvement of signaling pathways, cell division and intercellular interaction in cell differentiation during preimplantation development (Krivega et al., 2014, 2015b, 2015a). Lately a lot of attention was brought to the role of balanced genetics in functional cell. It was noted that similar gene expression changes trigger cellular stresses and defense mechanisms in different types of aneuploidy often interfering with cell differentiation. Recent work describes pathway networks deregulation in viable aneuploid cells (M. Krivega, et al., 2021).

Differences in sex development (DSD) are observed in patients with Turner (lacking Y chromosome: 45, X0) and Swyer (phenotypically females, genetically males: 46, XY) syndromes that are characterized by Dysgenetic Gonads (DG) and high cancer risk. We aim to identify the reasons behind the defects in gonads differentiation and whether they are connected to the genetic abnormalities per se.

Identifying the source of the phenotypes observed in cells with abnormal genetics is crucial for understanding the underlying molecular causes of aneuploidy syndromes. We aim to define several phenotypes that are shared by patients with different genetic syndromes. For this we measure specific transcriptional targets and analyze the proteome in primary patient’s samples, as well as develop new in vitro study models. We investigate the interaction of different cellular defense mechanisms that are potentially activated by genetic abnormalities. This includes DNA damage response, autophagy-lysosomal protein degradation and innate immune response. We address the relevance of this targets to the gonadal dysgenesis, cancerogenesis and infertility in general.

With our research we prove novel insights in understanding pathology of genomic syndromes and open additional opportunities for diagnostics and treatments.

Publications

Krivega, M., Essahib, W., and Van de Velde, H. (2015a). WNT3 and membrane-associated β-catenin regulate trophectoderm lineage differentiation in human blastocysts. Mol. Hum. Reprod. 21, 711–22. doi:10.1093/molehr/gav036.

Krivega, M., Geens, M., and Van De Velde, H. (2014). Car expression in human embryos and hesc illustrates its role in pluripotency and tight junctions. Reproduction 148, 531–544. doi:10.1530/REP-14-0253.

Krivega, M. V., Geens, M., Heindryckx, B., Santos-Ribeiro, S., Tournaye, H., and Van de Velde, H. (2015b). Cyclin E1 plays a key role in balancing between totipotency and differentiation in human embryonic cells. Mol. Hum. Reprod. 21, 942–956. doi:10.1093/molehr/gav053.

M. Krivega, C.M. Stiefel, S. Karbassi, L.L. Andersen, N.K. Chunduri, N. Donnelly, A. Pichlmair, Z. S. (2021). Genotoxic stress in constitutive trisomies induces autophagy and the innate immune response via the cGAS-STING pathway. Commun. Biol.

Team

Chemisch-Techn. Assistentin

  • Jutta Zimmer