lsromova 08.12.2019

Výzkum

Ústav biochemie a experimentální onkologie je vědecko-pedagogické pracoviště 1. lékařské fakulty Univerzity Karlovy v Praze. Jeho hlavním posláním je výuka studentů pregraduálního studia v magisterském studijním programu lékařství (v předmětech lékařská chemie a biochemie a dale patobiochemie) a rovněž v několika nelékařských bakalářských oborech. Stejný rozsah výuky, kromě bakalářského programu, je zajišťován i pro výuku v anglickém jazyce. Výuka v magisterském studijním programu lékařská chemie a biochemie zahrnuje základy fyzikální chemie, biochemii a molekulární biologii, biochemii tkání a orgánů a základy xenobiochemie. V povinně volitelném předmětu patobiochemie je výuka cílena na patobiochemickou problematiku kancerogeneze. Výuka studentů postgraduálního studia v doktorském programu v biomedicíně, se naší pracovníci podílejí jako členové oborových rad a jako školitelé na vedení PGS v oborech biochemie a patobiochemie a buněčná biologie, genetika a virologie. Pracovníci ústavu se dále pravidelně podílejí na výuce v předatestačních kursech pro lékaře v oborech radioterapie a onkologie.

Výzkumná práce je cílena především na oblast experimentální onkologie. Hlavní důraz je kladen na problematiku studia procesů významných pro kancerogenezi solidních nádorových onemocnění dospělého věku.

Výzkumné týmy na pracovišti:

Laboratoř biologie nádorové buňky/Laboratory of cancer cell biology (vedoucí: Aleksi Šedo)
Aktuální nabídka postgraduální studia

Laboratoř onkogenetiky/Laboratory of oncogenetics (vedoucí: Zdeněk Kleibl)

 

LABORATORY OF CANCER CELL BIOLOGY

Head:Aleksi Šedo

Research activities: The laboratory of cancer cell biology (LCCB) was established by Aleksi Šedo, M.D., PhD. in 1997 at the Institute of Medical Chemistry and Biochemistry as a joint laboratory of the 1st Faculty of Medicine, Charles University in Prague and the Institute of Physiology of The Czech Academy of Sciences. In 2002, LCCB joined the Institute of Biochemistry and Experimental Oncology and became its integral part. LCCB focuses on the role of membrane-bound serine proteases in various pathophysiological processes with a special focus on the pathogenesis of cancer and autoimmune disorders. Our results contributed to the definition of the group of “Dipeptidyl peptidase-IV structure and/or activity homologues” (DASH) and to the description of the expression pattern of DASH molecules in autoimmune rheumatoid diseases and in gliomas (CIT).

Currently, the main research interest is the role of the membrane bound proteases dipeptidyl peptidase-IV (DPP-IV) and fibroblast activation protein (FAP) in gliomagenesis. Gliomas are the most frequent primary intracranial tumors. The prognosis for the most common grade IV tumors (glioblastoma multiforme) remains dismal with a median survival of 14 months despite surgical resection and postoperative radiotherapy and chemotherapy. The identification and validation of qualitatively new therapeutic targets and approaches is therefore imperative to improve the limited therapeutic options. Analysis of the bioptic material, functional in-vitro assays as well as in vivo animal models including knock-out mice are being utilized to determine the role of DPP-IV and FAP within the tumor microenvironment and the interactions between malignant glial cells and the stroma with the aim of designing and testing inhibitors or inhibitor based targeting compounds as potential therapeutics.

LCCB closely cooperates with the neurosurgical departments of the Na Homolce Hospital and with the Military University Hospital and the Institute of Organic Chemistry and Biochemistry AS CR, v.v.i. LCCB is the founding member of the Neurooncological section of the Czech Oncological Society of the Czech Medical Association of J.E. Purkyně. The section should facilitate the national and international cooperation between clinical and biomedical disciplines that participate on the diagnostics, treatment and research of malignancies affecting the central nervous system. In addition to the neurooncology field, LCCB participates on the projects exploring the role of DPP-IV and FAP in the pathogenesis of pancreatic adenocarcinoma and possible effects of DPP-IV inhibitors on the immune system in patients with diabetes mellitus.

Publication list: see in PubMed

Our team and research interests:

  • Aleksi Šedo, M.D., Ph.D. (head) – role of proteases in cancer pathogenesis, gliomagenetic processess
  • Petr Bušek, M.D., Ph.D. – glioma cell invasion, proliferation, glioma stem-cells, targeting of FAP as a potential therapeutic approach
  • Eva Balážiová, M.D., Ph.D. – role of DASH molecules in glioma angiogenesis and microenvironmental interactions
  • Zdislava Vaníčková, M.D. – role of DASH molecules in pancreatic cancer and pancreatic cancer associated diabetes mellitus
  • Evžen Křepela, M.D., Ph.D. – proteases and protease inhibitors as regulators in cancer cell biology, enzymology of cancer cell apoptosis, role of proton dynamics in cancer cells.
  • Lucie Stollinová Šromová, Ph.D. - glioma stem-cells, immunosuppression in glioblastoma,  flow cytometry
  • Magdalena Houdová Megová, Ph.D. - expression profiling, immunosuppression and modeling of glioblastoma microenvironment
  • Marek Hilšer, Ph.D. - orthotopic xenotransplantations

Current grant projects:

  • Complex oncological program II. (2017, Charles University Research Development Schemes, project Progres Q28/LF1/1)
  • Novel Concepts for the terapeutic targeting of tumor microenvironment in human glioblastomas. (2015, Czech health research council - AZV ČR, project 15-31379A)
  • Study of PIWI-interacting RNAs in glioblastoma stem cells and their potential clinical implications
    (2019, Czech health research council - AZV ČR, project NV19-03-00501
  • Center for Tumor Ecology – Research of the Cancer Microenvironment Supporting Cancer Growth and Spread (reg. n. CZ.02.1.01/0.0/0.0/16_019/0000785) is supported by the Operational Programme Research, Development and Education
  • EATRIS project LM2015064

Our current Ph.D. students:

  • Michal Zubaľ (2017)
  • Rosana Mateu Sanz (2014)
  • Lenka Kotačková (2014, currently at maternal leave)
  • Ivana Matrasová (2010)
  • Petr Výmola (2019)

Our current undergraduate students:

  • Nikola Ternerová (2016)
  • Barbora Chmielová (2016)
  • Tereza Šváblová (2016)

Our finished Ph.D. students:

  • Radek Malík, M.D., Ph.D. (1999-2003; currently at The Czech Academy of Science)
  • Petr Bušek, M.D., Ph.D. (2004-2009; currently at our lab) ·
  • Jarmila Stremeňová, Ph.D. (2004-2009; Laboratory of Cell Signalling and Apoptotis, Institute of Molecular Genetics AS CR 2010-2014, currently at the Institute of Cellular Medicine, Newcastle University)
  • Eva Balážiová, M.D., Ph.D. (2006-2012; currently at the Dept. of Neurology and at our lab)
  • Lucie  Stollinová Šromová, Ph.D. (2006-2015; currently at our lab)
  • Marek Hilšer, M.D., Ph.D.  (2007-2016; currently at our lab)
  • Jana Trylčová, Ph.D. (2009-2018, currently at The Czech Academy of Science)

 

LABORATORY OF ONCOGENETICS

Head: Zdeněk Kleibl

Research activities: The laboratory has been established by Petr Pohlreich, M.D., PhD. in 1997. It investigates factors contributing to the development of hereditary cancer syndromes with the main focus on hereditary breast and/or ovarian cancer in the Czech population.

Breast cancer (BC) is the most frequent malignant cancer diagnosis affecting Czech female population. It has been estimated that ~5-10% BC cases arise in patients carrying pathogenic alteration BC susceptibility genes; however, the proportion of breast cancer cases influenced by genetic factors is probably much larger. The most frequent BC-susceptibility alterations are found in the two major breast cancer predisposition genes BRCA1 and BRCA2 that code for the large phosphoproteins involved in the dsDNA break repair.

Since foundation of the lab, we identified more than 550 carriers of pathogenic variants in BRCA1 or BRCA2 from 350 families. Our results show that BRCA1 represents the most frequently altered BC susceptibility gene in our population, while mutation in BRCA2 and other tested genes (including CHEK2, ATM, PALB2, p53, NBS1, RAD51C, RAD51D, PPM1D/Wip1, or STK11) participate to BC susceptibility in smaller proportion of high-risk patients (less than 40% of patients with identified pathogenic variant).

Except genetic analyses in the large population series of high risk and unselected cancer patients using classical genotyping as well as high-throughput next-gen sequencing approaches, the laboratory is also involved in functional in vitro analyses of identified variants. Our studies are focused on the analyses of DNA repair capacity following genotoxic insults in modified cells expressing altered genes that code for DNA repair proteins.

We were also involved in pharmacogenomic studies focused on analyses of hereditary variants in genes that code for proteins involved in fluoropyrimidines catabolic pathway. We described variants in these genes that may contribute to the development of serious and body site-specific toxicities in fluoropyrimidine-treated cancer patients.



Publication list: see in PubMed

Our team and research interests:

  • Zdeněk Kleibl, M.D., Ph.D. (head) – characterization of cancer susceptibility genes using NGS, pharmacogenomics studies.
  • Markéta Janatová, Ph.D. analyses of PALB2, RAD51C and RAD51D, NGS analyses of hereditary pancreatic cancer, clinical NGS data interpretation.
  • Petra Kleiblová, M.D., Ph.D.analyses of CHEK2, NGS-based identification of the tissue/disease-specific mRNA splicing, qPCR /HRM analyses, and the clinical interpretation of genomic data.
  • Jana Soukupová, Ph.D.analyses of ATM, NGS analyses in hereditary ovarian cancers
  • Jan Ševčík, Ph.D.functional in vitro studies of the DNA repair mechanics, analyses of UTR variants
  • Petra Zemánková, Ph.D. – NGS bioinformatics analyses, biostatistics
Current grant projects:
  • Variants of unknown significance in the CHEK2 gene: their functional classification and characterization of tumors in carriers of pathogenic mutations (2019-2023; Czech health research council, project NV19-03-00279) 
  • Classification of variants of unknown significance in cancer susceptibility genes by the multiplex PCR/NGS-based analysis of their impact on pre-mRNA splicing (2018-2022; Czech health research council, project NV18-03-00024)
  • Bioinformatics and functional analyses of susceptibility variants supporting the NGS-based testing of hereditary cancers in the Czech Republic (2016-2019; Czech health research council, project NV16-29959A)
  • Clinical classification of sequence variants in non-coding regulatory regions in breast cancer susceptibility genes (2016-2019; Czech health research council, project NV16-33444A)

Our current Ph.D. students:

  • Marianna Borecká (2013)
  • Lenka Stolařová (2015)
  • Klára Lhotová (Zdařilová) (2015)
  • Marta Černá (2017)
  • Jan Král (2018)
  • Zuzana Volková (2018)
  • Sandra Jelínková (2018)

Our current undergraduate students:

  • Sviatlana Paulich (2018)
  • Martina Dibalová (2017)

Our finished Ph.D. students:

  • Petra Zemánková (Boudová), Ph.D. (2013-2019; currently at our lab)
  • Jan Hojný, Ph.D. (2012-2019; currently at Dept. of Pathology)
  • Filip Lhota, Ph.D. (2010-2018; GENNET)
  • Martin Matějů, M.D., Ph.D. (2005-2014; Dept. of Oncology)
  • Jan Ševčík, Ph.D. (2004-2012; Brisbane University, Australia; currently at our lab)
  • Ondřej Havránek, M.D., Ph.D. (2008-2011; currently at MD Anderson, Houston, USA)
  • Ivana Tichá, Ph.D. (2008-2011; Linköping University, Sweden (2011-2014); currently at Dept. of Pathology)
  • Jana Soukupová (Prokopcová), Ph.D. (2004-2008; currently at our lab)
  • Markéta Prchalová (Brožová), Ph.D. (2004-2008; currently at maternal leave)
  • Eva Scholzová (Vondrušková), Ph.D. (2004-2008)
  • Markéta Janatová, Ph.D. (2001-2005; currently at our lab)
  • Michal Zikán, M.D., Ph.D. (2000-2004; currently at the Dept. of Gynecology and Obstetrics)


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