Science and research

Grant Projects (ongoing in the year 2017)

View ongoing grants in the year: 2009, 2010, 2011, 2012, 2013, 2014, 2015, 2016, 2017, 2018, 2019, 2020, 2021.

The role of hepcidin in regulation of systemic and myocardial iron metabolism in heart failure (2015-2017, GA0/GA)

GA ČR 15-14200S [2015 – 2017]

RNDr. Jiří Petrák, Ph.D., 1. LF UK Praha
doc.MUDr. Daniel Vyoral, CSc.

Iron deficiency is observed in 50 percent of patients with heart failure. The deficiency is not only implicated in development of anemia in heart failure, but also in the depletion of iron in myocardial tissue. Depletion of cardiac iron can contribute to the disease progression. However, causes and molecular mechanisms involved in the systemic and cardiac iron deficiency in heart failure are unknown. Tissue and body iron regulation is orchestrated by the peptide hormone hepcidin which is therefore central to this project. In addition to the effect of circulating hepcidin, autocrine/paracrine effect of cardiac hepcidin expression may play an important role in the iron homeostasis of cardiac muscle. Our aim therefore to elucidate the function of systemic and cardiac hepcidin in local iron homeostasis in heart failure. Combined study of cultured rat cardiomyocytes, rat model of heart failure and explanted human hearts should provide complex insight into the processes.

Nanobiophotonics for future health care (2012-2018, GA0/GB)

GA ČR P205/12/G118 [2012 – 2018]

doc. Ing. Jiří Homola, CSc., DSc., Ústav fotoniky a elektroniky AV ČR
prof. Ing. Jan E. Dyr, DrSc.

As modern medicine evolves towards quantitative and molecular based science, biophotonics is envisioned to play an increasingly important role in multiple areas of medicine, contributing to quality of health care, reduction of health care costs, and sustainability of the medical care in the ageing society. The proposed project aims to advance research in selected areas of nanobiophotonics with focus on photonic molecular biosensors based on plasmonic nanostructures. The main areas of research in this project include research into plasmonic phenomena on metallic nanostructures, development of novel tools for analysis and design of plasmonic nanostructures, fabrication and experimental characterization of plasmonic nanostructures with potential for surface plasmon resonance (SPR) and surface-enhanced Raman scattering (SERS) sensing, interfacing biomolecules with inorganic nanostructures and investigation of interactions between such biophotonic structures and biological samples, and realization of SPR and SERS biosensors for detection of biomarkers of onco-hematological diseases.

Development of methods for cellular and gene therapy of hematological malignancies

AZV 15-34498A [2015 – 2019]

MUDr. Pavel Otáhal, Ph.D., VFN Praha
RNDr. Šárka Němečková, DrSc.

Significant progress in the field of tumor immunotherapy has been recently shown to complement available treatment modalities of hematological malignancies. This novel treatment method is based on the use of adoptively tranferred T lymphocytes which were modified in vitro prior to transfer to express artificial signaling molecule designated Chimeric Antigen Receptor (CAR) which redirects the specificity of modified lymphocytes to surface antigens expressed by malignant cells. In this project we propose to develop methods for CAR-based therapy of lymphomas and leukemia. Next, we propose to develop methods for selective expansion of T cells specific for EBV, HCMV or adenovirus from donor lymphocytes for the use in patients who received allogeneic stem cell transplantation and as a result of immunosupresion developed acute viral infection. The goal of the project is the manufacture of GMP-grade cells and their pre-clinical testing.

National study of leukemia cell mutations and clonality in patients diagnosed with acute myeloid leukemia

AZV 15-25809A [2015 – 2018]

Doc. MUDr. Zdeněk Ráčil, Ph.D., FN Brno
prof. MUDr. Petr Cetkovský, Ph.D., MBA

Molecural analysis at diagnosis and following monitoring of specific gene aberrations represent a standard part of a diagnostic-therapeutic process, especially in cytogenetically normal acute myeloid leukemia (AML) patients. Besides the routinely tested markers with clear prognostic importance, other gene mutations were recently identified. The new generation sequencing allow us to uncover the frequency of these recently described mutations in a very large cohort of AML patients from all major hematological centres in the Czech Republic, and to find coexisting mutations with high benefits of such testing in patients. The possibility to define separate leukemic clones in individual patients will further enable the monitoring of their status in the course of the disease and to elucidate the disease clonality. The study of these effects will be supported by xenotransplantation experiments analyzing engraftment of the samples with known clonality. AML patients bearing mutations in the DNA methylation regulators will be examined for subsequent DNA methylation and gene expression analysis.

Molecular detection of chronic myeloid leukemia using patient-specific BCR-ABL1 genomic fusions: impact on effectiveness of treatment management

AZV 15-31540A [2015 – 2018]

Mgr. Kateřina Machová Poláková, Ph.D.
Doc. MUDr. Jan Zuna, Ph.D., 2.LF UK Praha, Mgr. Tomáš Jurček, FN Brno

DNA level with the aim to obtain more precise information on the course of CML at the molecular level in particular stages of the treatment with tyrosine kinase inhibitors (TKIs) than standard monitoring of BCR-ABL1 transcript level. We will study the hypothesis that the level of BCR-ABL1-positive cells at the time of diagnosis and early after treatment initiation stratifies patients who achieve stable deep molecular response, and patients who are at risk of treatment failure and who may benefit from an early treatment switch. We suppose that the quantification of BCR-ABL1 at the DNA level plays a crucial role in the TKI therapy discontinuation in patients in deep molecular response. The outputs of the project will contribute to the personalization of therapy using patient-specific molecular diagnostics having positive socioeconomic impact on the CML treatment. The aim of this project is to establish patient-specific assays for BCR-ABL1 quantification on DNA level and to determine at which phases of CML treatment the quantification of BCR-ABL1 genomic fusion provides valuable data improving individualized management of the therapy.

Study of epigenetic factors and tumor-suppressor genes regulating oncogene signaling pathways in models of leukemic hematopoiesis

LH15104 [2015 – 2017]

Mgr. Kateřina Machová Poláková, Ph.D.

The aim of the proposed project is a bilateral collaboration of the Czech and American research institutes on basic research study of hypothetical signaling pathways that are deregulated in leukemic stem and progenitor cells on model cell lines and primary cells of patients. This project is specifically aimed to elucidate molecular mechanisms and signaling pathways used by BCR-ABL positive leukemic hematopoietic stem and progenitor cells for their survival, self-renewal, proliferation and resistance to current therapy, causing transformation to deadly blast crisis. This is essential for understanding leukemic cell behavior and identifying proper molecular targets for new therapeutic agents targeting leukemic stem cells and with a potential to cure disease.

Anti-tumor effects of chelation therapy in myelodysplastic syndrome and identification of new therapeutic biomarkers

AZV 16-31689A [2016 – 2019]

doc. MUDr. Jaroslav Čermák, CSc.
Doc. RNDr. Vladimír Divoký, Ph.D., LF UP Olomouc

Myelodysplastic syndrome (MDS) is a clonal disorder characterized by ineffective hematopoiesis and increased risk of transformation to leukemia. Low-risk MDS patients are typically transfusion dependent, and their chelation therapy not only removes surplus of toxic iron stores, but has also antiproliferative and proapoptotic effects on tumor cells. Our preliminary data revealed an activation of DNA damage response (DDR) signaling and induction of apoptosis in pluripotent stem cells exposed to iron chelator in vitro. In vivo, 6-week applications of chelator to preleukemia mice lead to a decrease of actively replicating myeloid cells and an activation of G2/M checkpoint. Correspondingly, we observed an activation of stress signaling pathways in CD34+ cells from low-risk MDS patients receiving chelation therapy. We propose: to elucidate how iron chelation reinforces DDR and cell cycle checkpoints in oncogene-positive pre-leukemia cells in vivo; to identify biomarkers in MDS useful in clinical practice, allowing the prediction of a positive effect of chelation therapy for leukemia free survival.

Application of high-throughput technologies for screening of plasma circulating microRNAs in myelodysplastic syndromes

AZV 16-33617A [2016 – 2019]

Ing. Michaela Dostálová Merkerová, Ph.D.

Circulating micorRNAs (miRNAs) are new promising semi-invasivemolecular markers of various types of cancer. However, little information is known about their deregulation in myelodysplastic syndromes (MDS). Nowadays, the diagnosis of MDS is based on morphological evidence of bone marrow dysplasia. In the proposed project, we will employ next-generation sequencing for the screening of circulating miRNAs in plasma samples from MDS patients. Comparison of plasma miRNA profiles i) in untreated MDS patients with various disease subtypes, ii) in different risk categories, and iii) in MDS patients during treatment will enable to select circulating miRNAs with altered levels associated with the course of the disease. The genome-wide analysis followed by a validation phase performed by digital PCR on the level of particular preselected miRNAs aims to identify novel semi-invasive molecular markers suitable for monitoring of MDS patients, finally contributing to the prevention of the disease progression, an increase of survival, and an improvement of patient comfort.

Integrative analysis of genomic changes in DNA repair systems in myelodysplastic syndrome and their relevance in the pathogenesis

AZV 16-33485A [2016 – 2019]

RNDr. Hana Votavová , Ph.D.

Myelodysplastic syndrome is charactererized by a high heterogeneity of clinical course and an increased risk of development of acute myeloid leukemia. We assume that the as yet unexplained mechanism of the disease, leukemia transformation and a large number of mutations detected recently may be related to a decreased function of DNA repair systems, which under physiological conditions form an effective protective barrier against malignant transformation of cells. The project will monitor changes in 84 genes involved in DNA repair mechanisms at the level of genome, transcriptome and proteome, and reparative cell activity using in vitro assays. Due to the clonal character of the disease, the changes will be observed mainly in pluripotent hematopoietic CD34+ bone marrow cells. Data obtained using modern molecular genetic techniques such as targeted next generation sequencing will be closely correlated with clinical data of the patients.The proposed project aims to identify new molecular biomarkers involved in the formation and progression of the disease and to find new potential therapeutic targets.

Mutated nucleophosmin as a potential target for immunotherapy of acute myelogenous leukemia

AZV 16-30268A [2016 – 2019]

RNDr. Kateřina Kuželová, Ph.D.

Nucleophosmin (NPM) C-terminalmutations are detected in about 30% of patients with acute myeloidleukemia (AML). Our pilot study indicated that individuals with appropriate HLA alleles (about 85% of population) are able to raise a spontaneous immune response against mutated NPM which can prevent AML development. Anti-NPM immune response is also active during therapy and essentially contributes to a better outcome of patients having NPM mutations. The objectives of the project are: (i) to confirm and to extend these findings on a larger patient cohort, (ii) to obtain experimental evidence of the existence of NPM-specific T-cells, (iii) to establish diagnostic methods for the detection of reasons for transient or complete failure of the immune response which allows for AML development. The practical aim of this applied research is to prepare conditions for the implementation of individualized immunotherapy into the treatment regimen of AML patients in order to achieve the disease eradication.

Adoptive immunotherapy of hematological malignancies in elderly patients: preclinical and clinical study

AZV ČR 16-34405A [2016 – 2019]

MUDr. Petr Lesný, Ph.D.

Innovative immunotherapy approaches, such as administration of haploidentical natural killer (NK) cells with phenotype changed by cytokine induction or with molecular genetic methods, are being extensively utilized in the therapy of hematological malignancies, such as acute myeloid leukemia (AML). Our project aims at the combination of these two methods, using the cytokine induced killer (CIK) cells genetically modified in order to express chimeric antigen receptors targeting suitable AML targets, such as CD123. We expect a cumulative effect of these two modifications, increasing the specific cytotoxic effect of the administered cells without increasing their toxicity. During the project, we plan to obtain sufficient preclinical and clinical supportive data in order to submit ambitious clinical trial of gene modified CIK cells in the therapy of AML. This approach will be useful in elderly patients, where the chemotherapy is less effective and limited by comorbidities.

Analysis of the role of PAK family kinases in the regulation of hematopoietic cell interaction with extracellular matrix proteins

GA ČR 16-16169S [2016 – 2018]

RNDr. Kateřina Kuželová, Ph.D.

PAK family belongs to key regulators of processes involving cygoskeleton work, such as cell adhesion, targets in various diseases, including tumors. The majority of the current knowledge about PAKs is limited to PAK1 function in adherent cells. PAK1 is often overexpressed in invasive solid tumors and its high activity correlates with poorer patient prognosis. Recent works and our preliminary experiments show that in hematopoietic cells, PAK2 is a very important member of the family and can have distinct and even opposing effects to PAK1, despite of a high sequence homology. Using a complex approach involving both original and established methods (e.g. microimpedance measurement, interference reflection microscopy, exogenous expression of fluorescently tagged proteins, western-blotting) we aim to elucidate the role of group I PAKs in regulation of hematopoietic cell binding to the extracellular matrix, to find differences between PAK1 and PAK2 and check for possible PAKs interaction with Lyn kinase.

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Ústav hematologie a krevní transfuze
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