Today, numerous mitochondrial and nuclear pathogenic gene defects causing mitochondrial disease have already been identified. More recently, our attention has turned towards protein synthesis in mitochondria.
Malformations of cortical development (MCD) represent a major cause of developmental disabilities and severe epilepsy. Polymicrogyria (PMG) is a heterogeneous condition, with respect to both phenotype and genotype. In the first part of the project the genetic basis of PMG is addressed. The second part of the study aims at improving the phenotypic characterization of MCD in order to facilitate further genetic research.
The research carried out under Inge Liebaers has traditionally had a strong focus on all aspects of reproductive genetics..
Within reproductive genetics, the genetic causes of male infertility is a first topic of interest. To elucidate genetic causes of male infertility, genes with a testis-specific expression pattern will be examined and the whole genome will be investigated for the presence of deletions/duplications. Treatment of male infertility is a logical complement of the former topic. A specific subpopulation of male infertile patients are survivors of childhood cancers who underwent aggressive treatment including chemo- and radiotherapy and bone marrow transplantation. Studies to investigate the genetic and epigenetic aspects of spermatogonial stem cell (SSC) transplantation as well as cryopreservation and tissue expansion are mandatory before a clinical application becomes feasible.
Another route to mature sperm would be by differentiation of human embryonic stem cells (hESC) into spermatozoa. As a way to elucidating the pathways controlling differentiation into SSC, dedifferentiation of SSC into pluripotent cells (PC) will be attempted.
Safety of assisted reproductive technology (ART), and more specifically at the level of epigenetics and genomic imprinting, is another firm link between reproduction and genetics. We have developed in-house methods for the analysis of DNA methylation on small samples, typically one embryo.
Although the majority of children born after assisted reproductive technology (ART) are healthy, recent years have seen the publication of several papers that report on the association of ART and imprinting disorders. Data obtained will subsequently be linked in an anonymous way to the neonatal data obtained from the follow-up study of IVF/ICSI children.
Understanding totipotency at the cellular and molecular level will have a great impact on the knowledge of preimplantation development and may have important implications for the current practice in the IVF lab.
Although PGD has been part of everyday clinical routine at UZ Brussel since the mid-nineties, we still aim to improve the technology. The combination of several emerging technologies will be evaluated and clinically implemented.
Concurrently, data mining of the past 15 years of clinical PGD, will allow for retrospective analysis of PGD data.
Clinical research on children born after different ART techniques was started since the introduction of IVF at the UZ Brussel (1983). In the future, studies on (inherited) male infertility in boys born after ICSI will be performed once they reach 18 years in the next few years and the safety of many new techniques (PGD, cryopreservation and vitrification) will be evaluated through the health of the offspring. Other possible risks of ART techniques for the offspring will be examined on the older children of the cohort.
Human embryonic stem cell research (HESC) has been established in our group in 2002 and has already led to interesting results and publications. We have currently derived 26 different HESC lines, of which 16 carry a SGD. The great value of these cells for research into fundamental embryology and the molecular basis of the SGD they carry is beyond doubt. We wish to further expand our possibilities for the procurement of pluripotent cells, such as induced pluripotent cells, from different sources.
Preliminary results have shown that our hESCs accumulate different types of chromosomal abnormalities, ranging from the amplification of known "stemness genes", ie genes involved in pluripotency, to large deletions and duplications.
We will explore the causes of these abnormalities by the study of the gene expression.
Differentiation into endodermal and mesodermal derivatives will for a large part be carried out in collaboration with other groups. In our own lab, we will attempt to differentiate hESC into mature lung cells, using a liquid-air interface culture system that we have previously developed. Differentiation in normal hESC will be compared with differentiation in hESC carrying a SGD affecting primarily muscle (DM1, FSHD, DMD) or lung (CF).
The CRM vitrification project will encompass three fields of application: embryos, oocytes and in extension, pluripotent cells.