Laboratory for inherited metabolic disorders

The specific goals are:
A. study of mechanisms and treatment of cancer and infectious diseases;
B. establishment of national platform for chemical biology and drug design;
C. identification of new targets, biomarkers and diagnostic approaches leading to individualized therapy;
To achieve its goals, the BIOMEDREG will take advantage of the close links with the Project Partners: i) the major regional hospital – the University Hospital in Olomouc (UHO, thereby providing direct access to clinical material and potential clinical trials), and ii) the internationally highly competitive Czech chemistry and biochemistry centers: Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences (IOCB) and Institute of Chemical Technology Prague (ICT), which will directly participate in the Project, and are highly complementary to the mission of the BIOMEDREG, providing unique compound libraries and know-how for the BIOMEDREG Centre in Olomouc and the unifying focus on biological chemistry applied to pathogenetic pathways and drug discovery. The BIOMEDREG infrastructure will be joined workplace of the four institutions located in the eligible region of the Czech Republic (Olomouc), and within an easy reach of the major biomedical and chemical campuses in the country.

Primary objective:
To establish a new institute (Institute of Molecular and Translational Medicine at Faculty of Medicine and Dentistry, Palacký University in Olomouc), technological infrastructure and platform for molecularly-oriented basic and translational biomedical research, aiming at better understanding of molecular bases of cancer and infectious diseases, leading to discovery of new biomarkers and therapeutic targets, followed by validation of biological activities of small molecules identified in high-throughput screening, preclinical testing and proof-of concept clinical trials. Infrastructural part of the project will concentrate in common platform individual core facilities with unique technologies, and will consist of 5 core facilities (Bioinformatics and Biostatistics, Animal Models, Genomics, Proteomics and Cell Biology Core Facility) that provide key technical services to Applicant, Partners and external users.

Secondary objectives:
To establish a network encompassing top-level research groups in biomedicine and translational medicine, chemical biology and medicinal chemistry;
1. To enhance and expand the capabilities of the Palacky University to serve as a major regional referral resource for advanced medical diagnostics, prevention and therapy;
2. To integrate Central Moravian and Czech scientists into top-level research consortium;
3. To improve technological platforms of science in the Czech Republic;
4. To bring together experts in molecular sciences and translational medicine;
5. To educate pre- and postgraduate students and to attract young investigators by providing an intellectually and technologically highly stimulating environment;
6. To offer expertise for biotechnological, chemical and pharmaceutical industry and to create opportunities for development of innovative companies in the region;
7. To further promote the existing collaborations and integration within European and global research initiatives.
The main end users will be the scientific community, students, biopharmaceutical and health care industry and patients.

Milestones and expected results:
Milestones: Start of the project (04/2010), Tenders and purchase of investments (04/2010-11/2013), IMTM building development (09/2010-12/2012), Start of research programs (04/2010), Final building approval (12/2012), Start-up of research works at the IMTM building (01/2013), End of the project (03/2014), Start of the monitoring period (04/2014), End of the monitoring period (03/2019).
Expected results: Proposed project will provide unique information on pathways and molecules acting as barriers against cancer, their deregulation during tumorigenesis, infectious diseases, disease resistance to current therapies, etc. It will further identify drugable targets and provide a unique platform for identification of novel chemical entities with potential use as structural motifs for new drugs. The detailed biological understanding of molecular pathologies will further promote the development of unprecedented diagnostic, prognostic, and therapeutic strategies.

List of research programmes:
1. Molecular basis of diseases and molecular targets
2. Medicinal chemistry
3. Chemical biology and experimental therapeutics
4. Biomarkers - identification and validation
5. Pharmacology and Toxicology
6. Translational medicine

Analysis of metabolome profile in model of cancer stem cells, BCR-ABL positive cell lines sensitive and resistant to imatinib and cells obtained from patients with chronic myeloid leukemia and myelodysplastic syndrome treated with tyrosine kinase inhibitors or iron chelators enable to identify metabolomic markers of optimal treatment response and resistance and mechanisms by which iron chelators influence the cell cycle of cancer cells. Results obtained will be used for prognostic refinement and individualization of targeted treatment in patients with above-mentioned hematopoietic disorders.

Oncogenic transcription factors and signaling pathways in leukemic transformationDeregulation of cell cycle and apoptosis in leukemias and lymphomasAcquired and congenital defects of erythropoiesis (anemias and polycythemias)Hematopoietic stem cells; Tumor-host interactions in hematological malignancies.

The aim of project is to clarify the further causes of resistance to imatinib in patients with chronic myeloid leukaemia that are associated with transport mechanisms influencing the intracellular levels of the drug.

The main goal of our project is to build tools for metabolomic diagnosing of inherited metabolic disorders in children. On the basis of previous research results establish R&D collaboration between Palacky University in Olomouc (Laboratory for Inherited Metabolic Disorders) and University of Science and Technology in Trondheim (Department of Biotechnology, Group of Metabolomics). Transfer of metabolomic know-how from partner to applicant. Develop and validate methods for metabolomic analysis human cells in culture. Development of human metabolomic GC-MS and LC-TMS spectral libraries. Define metabolome of human skin fibroblast in culture of healthy individuals. Analyze metabolome of human skin fibroblast in culture from patients with defined inherited metabolic disease. Realize results of collaboration by publishing 3 scientific papers in international scientific journals. On the basis of the project prepare subsequent projects and further collaboration.

Purines are synthesized de novo in the ten-step metabolic pathway. So far, only two defects have been described. The aim of this project was to develop methods capable of monitoring human de novo synthesis of purines and to identify these defects at the metabolite level. Methods of incorporation of stable and radioactive isotopes were used in conjuction with microscale separation techniques, advanced techniques of mass spectrometry and 500 MHz NMR. By these methods we studied metabolite effects of these defects on the CHO cell lines model and Saccharomyces cerevisiae defective in purine de novo synthesis. Subsequently, the methods were applied to body fluids and cells of patients who might be affected by these defects.