Research

Transgenic model, metabolism, craniofacial development, gastrointestinal tract

Ubiquitylation-mediated processes in health and disease
Using mutant mouse models we are addressing the role of several ubiquitin ligases whose function and role have not been described – the field of Ub-ligases and deubiquitinases is of key importance for cellular processes and many of the genes in the Ub-ligase and deubiquitinase families (altogether around 900 members) have not been investigated so far, or investigated only poorly. A major focus of these studies is to understand the role of ubiquitination in regulating intestinal barrier function, immunity, and to characterize links with human inflammatory bowel disease. In our current work we focus on cullin-RING ubiquitin ligases involved in GIT homeostasis and pathological processes since the cullin family has been largely associated with different types of cancer in GIT and thus represents a promising pharmacological target. We use RNA in situ hybridization, qRT-PCR and LacZ reporter systems to localize expression of components of cullin-RING –ubiquitin ligase complexes together with conditional transgenic models to specifically assess the role of cullin dependent ubiquitination in GIT. We are studying also other U3 ligases using conditional, mouse models, among them Btbd3, , Rnf121, Rnf186, Cul4a, Ddb1, Cul3 and others.

Functional redundancy of the kallikrein locus
The mammalian kallikrein gene cluster exists as a gene cluster (on chromosome 19 in humans) comprise a class of extracellular proteases that mediate tissue homeostasis. They are often dysregulated during cancer and can serve as excellent diagnostic markers.
We are addressing the functional redundancy of kallikreins by introducing two or more concurrent gene deletions. We expect these experiments not only to resolve the role of kallikreins in important physiological functions such as wound healing, but also to yield insight into their epigenetic co-regulation.

Molecular mechanisms of craniofacial development
Our focus is to investigate the the molecular mechanism driving the fascinating complex process of craniofacial development  . In our current research we are focused on unveiling molecular regulation of collective epithelial migration as important process of epithelial morphogenesis and involvement of  ubiqitin dependent proteolytical pathways in regulation of morphogenetic signalling cascades.  Recently described Wnt- signalling modulator Trabd2b is known to be responsible for cleavage of the last 8 N-terminal residues of selected canonical and non-canonical Wnt ligands. This transmembrane manganese-dependent metalloproteinase plays a crucial role in orchestration of Wnt signalling pathways activity during early embryonic development and specially during neural tube closure and head development. Trabd2b deficient mice display variety of  neural tube defects, pointing out the importance and complexity of Trabd2b role in embryogenesis. The importatnt feature of craniofacial area is development of mineralized tissues such as teeth and bones. The molecular mechanisms covers the differentiation events of mineral producing cells, secretion and maturation of extracelular matrix and finally crystalization process of hydroxyapatite. We focus on function of extracellualr protein Ameloblatin in regulation of mineralization processes in tooth enamel formation and bone homeostasis process. With our aim to study mineralization processes we also take advantage of International Mouse Phenotype Consortium and we focus on deeper analysis of novel mutants with mineralization defects. One of the gene studies is Fam46a.  FAM46A loss of function mutations have been found in patients with osteogenesis imperfecta. In our lab we generated a Fam46a knock out mice to characterize the molecular mechanisms that underlie the observed phenotypic changes and determine its connection to rare human diseases.   

Role of Cluh protein in metabolism regulation
The mRNA binding protein CLUH is key in the mitochondrial proteome, as it binds to more than 400 mRNAs. The Brown Adipose Tissue (BAT) is known for the high number of mitochondria, It is stimulated under cold exposure and it is important after birth due to the cold environment.  It remains unclear the mechanisms underlying the lipids and glucose uptake to produce heat, and CLUH might be playing an important role in this process. This project also aims to elucidate the importance of CLUH in adipocyte differentiation and mitochondrial biogenesis.

 

Last change: October 22, 2019