Description
Fibrosis has implication for the most common diseases like hypertension, myocardial infarctions and malignant neoplasm. MOMENTO is a partnership that builds capacity and enhances knowledge between Poland and Norway on fibrotic mechanisms. The objective of the project is to understand the detailed mechanism of fibrotic processes. Identification of genes and proteins for use in early detection for prevention and treatment strategies will bring forward applications in both medicine and biotechnology. Characterization of the early fibrosis mechanisms will become the basis for the new method development of diagnosis and treatment of fibrosis. The target groups are: elderly people, PhD students and post-doctoral fellows and researchers. Poland provides expertise in molecular biology leading to identification of early fibrotic markers in cells undergoing EndMT whereas Norway - genetically modified mice and use of these in a new autoimmune model of fibrosis to evaluate role of collagen receptors in fibrosis.
Summary of project results
Partner search lead to establishment of contact between prof. D. Gullberg with prof. C. Cierniewski and the mutual agreement on composing a research plan focusing on fibrosis was made. The Polish partner would focus on the role of the Snail and take advantage of integrin 11 reagents from Gullberg laboratory to evaluate EMT events and the mesenchymal phenotype. The Norwegian partner would establish a model of dermal fibrosis using the integrin 11-/- mice and analyze cellular and molecular mechanisms by which integrin 11 interacts with collagen I in the dermis. A major drawback was the sudden passing of Prof. Cierniewski, but despite of this, both partners have continued the work as originally planned. A major problem for the Polish partner has been difficulties to generate stable snail transfectants. For the Norwegian partner the mouse model has caused problems (an alternative model had to be used). However, both partners have managed to produce results that will be of value, but will depend on future funding in order to eventually be published. The Norwegian partner has established that dermal fibrosis in the bleomycin mouse model is attenuated in the absence of integrin 11. Cellular and molecular analysis has indicated that integrin 11 interacts with the non-canonical TGF- pathway to regulate collagen remodeling in a JNK- and TAK1- dependent manner. Careful analyses of the ITGA11 promoter furthermore lead to the identification of a mechano-sensitive SMAD-binding element as being involved in the regulation of integrin 11 levels. The Polish partner has explained the molecular mechanisms of tissue fibrosis in early stages of EndMT induced by TGF-β and/or Snail in the HMEC-1 cells. The obtained data suggest that: palladin and fibrosin could be a new biomarker in the early stages of EndMT; modifications of tubulin isoforms are implicated in properly N-cadherin localization; reorganization of cell morphology and contraction is regulated mainly by MRTF-A activation and is dependent on ILK and MMP-9 pathway; PDI can interact not only with integrin subunit type β3, but also with integrin α11; an intermediate of EndMT stages is dependent on both ECM degradation and PILS formation associated with MMP-2 proteolytic activity and Rho/ROCK cytoskeleton contraction. In summary, we are grateful for the funding received through this grant. No immediate plans for continued collaboration beyond research program MOMENTO exist at the moment.
Summary of bilateral results
The MOMENTO project is an excellent example of bilateral cooperation. The Norwegian partner has made yearly visits to Lodz and listened and commented on projects in all work packages. This input from Norwegian partner has been extremely useful for Polish researchers. For the other hand Polish side enhance knowledge of role of α11β1 in endothelial to mesenchymal transition (EndMT). Polish partner provided expertise in molecular biology leading to identifying early fibrotic markers in cells undergoing EndMT. The MOMENTO project was created with the intention of gaining better understanding of the importance of endothelial to mesenchymal transition in fibrosis, and this goal was achieved, as we: - Identified two biomarkers of fibrosis; fibrosin and palladin - Broadened our understanding of the animal models - Learned about experimental procedures on animal models - Introduced the floating gel methods in MUL laboratory. Norwegian partner invited PI´s from Poland to attend yearly conference organized by National Centre of Excellence where Norwegian partner is PI. Attending this high quality international CCBIO Solstrand conference has been valuable for attending Polish PI´s. MOMENTO has been represented by poster at the poster session of these meetings. Researchers from Poland visited University of Bergen. During those visits Norwegian partner have shared reagents, protocols, and "know how". Because MOMENTO combined a group of laboratories with different expertise ranging from biochemistry, molecular biology, medical biology, cell biology and expertise in transgenic techniques, it was possible to achieved innovative results in the field of fibrosis.