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Grant Projects (ongoing in the year 2018)
View ongoing grants in the year: 2009, 2010, 2011, 2012, 2013, 2014, 2015, 2016, 2017, 2018, 2019, 2020, 2021, 2022, 2023, 2024, 2025, 2026, 2027, 2028.
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 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]
doc. 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.
Anti-tumor effects of chelation therapy in myelodysplastic syndrome and identification of new therapeutic biomarkers
AZV 16-31689A [2016 – 2019]
prof. 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]
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]
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.
Long non-coding RNAs in myelodysplastic syndromes: clinical relevance and implication in the pathogenesis
AZV 17-31398A [2017 – 2020]
Ing. Michaela Dostálová Merkerová, Ph.D.
Doc. Ing. Jiří Kléma, Ph.D., FEL ČVUT Praha
Long non-coding RNAs (lncRNAs) regulate hematopoietic lineage differentiation at almost every stage and their abnormal expression may contribute to various hematopoietic disorders. They may become useful diagnostic and prognostic markers contributing to detection of the MDS progression and increase of the patients' survival, and even potential therapeutic targets in future. In the proposed project, genome-wide screening of lncRNA levels in MDS patients will be employed to compare expression profiles between various risk groups of patients with the aim to find lncRNAs with significantly different levels and relevance to MDS diagnostics. Because the knowledge about individual lncRNAs is often limited to the simple transcript annotation, the causes, roles and consequences of deregulated lncRNAs in the pathogenesis of MDS will be studied by experimental and computational approaches.
Phenotype and function of head and neck squamous cell carcinoma immune cells as predictive markers of clinical response
AZV 17-28055A [2017 – 2020]
RNDr. Ruth Tachezy, Ph.D., PřF UK Praha
RNDr. Eva Hamšíková
The aim is to identify the prognostic factors in patients with head and neck squamous cell carcinoma ( HNSCC) to improve the predictivity of the clinical response to the available therapeutic options. A comprehensive comparative analysis of infiltrating and circulating cells of the immune system will be done in patients with HPV-associated and non-associated tumors. A specific aim of this study is to consider the role of the immunosuppressive regulatory CD4+ T cells and PD-1+CD8+ T cells and their newly identified subtypes, and the importance of the expression of the pro-angiogenic VEGF. The predictive potential of the level of expression of specific molecules in epithelial tumor cells and tumor-associated plasmacytoid dendritic cells (pDCs) will be studied. One hundred retrospective paraffin-embedded biopsy specimens and cca 150 prospective fresh biopsy tissue specimens and blood samples from HNSCC patients will be investigated by multicolor immunohistochemistry, PCR, mass cytometry, and function tests. Peripheral blood parameters of immunity will also be monitored after therapy.
Identification and monitoring of prognostic and predictive molecular markers in patients with low risk myelodysplastic syndrome
AZV NV18-03-00227 [2018 – 2021]
Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal diseases with ineffective hematopoiesis and a higher risk of transformation to acute myeloid leukemia. The early stages of MDS can be considered a premalignant condition with relatively good prognosis. Despite this, some patients experience disease progression and shorten the overall survival time. In this project, we will focus on the identification of specific mutations at the time of diagnosis in patients with low risk MDS that would predict the disease progression. We will perform a mutational screening in retrospective paired samples of progressing patients and those without progression. We will carry out a prospective mutational study in patients with detected unfavorable mutations and monitor the dynamics of mutational burden using sensitive droplet digital PCR. To complete background of the progression process, we will perform a comparative analysis of mRNA expression profiles of patients' serial samples. Introduced methods will refine the patient's prognosis, allow progression prediction and optimize treatment
Epigenetic, genetic and molecular factors required for mutagenesis of oncogene BCR-ABL1 during Ph+ cells treatment with tyrosine kinase inhibitor
18-18407S [2018 – 2020]
doc. Mgr. Kateřina Machová Poláková, Ph.D.
The successful therapy of chronic myeloid leukemia (CML) is based on targeted inhibition of BCR-ABL1 kinase activity by specific inhibitors (TKI), preferentially by imatinib in the first line treatment. Mutations in the BCR-ABL1 kinase domain represent a quite frequent mechanism of acquired resistance to the TKI therapy. We hypothesize, that development of TKI resistance by acquisition of BCR-ABL1 mutations during imatinib treatment is not just passive process of selection of preexisting mutated clones. BCR-ABL1 mutations may be acquired de novo, requiring a sublethal concentration of imatinib in concert with intrinsic epigenetic, genetic and molecular factors enabling to escape of subclones in early apoptosis from cell cycle control and DNA reparation process. We expect that identified molecules and connected nodes of the networks required for resistant phenotype may be potentially druggable and useful for early prediction of predisposition of CML cells to acquire BCR-ABL1 mutations.
Očkování proti HPV u pacientů s rekurentní laryngální papillomatózou – je možné zlepšit kvalitu jejich života?
Merck & Dohme s.r.o. IIS ID 37651 [2011 – 2021]
RNDr. Ruth Tachezy, Ph.D.
MUDr. Jitka Vydrová – Medical Healthcom., s.r.o.,, Hlasové centrum, Praha
Klinická studie fáze III b. Hlavním cílem studie bude ověřit vliv očkování tetravalentní HPV vakcínou na vznik rekurentních papillomatozních lézi a interval remisí u pacientů s RRP. Vedlejšími cíli bude zjištění typu HPV v lézi RRP, sledování hladin protilátek proti HPV antigenům obsaženým ve vakcíně, případně složkám imunitního systému v odebraném s
Analysis of T cells specific for BK polyomavirus and Adenovirus in haploidentical transplant recipients with hemorrhagic cystitis
AZV 17-31593A [2017 – 2021]
The aim of the proposed project is to analyse risk factors contributing to recently recorded elevation in number of cases of haemorrhagic cystitis (HC) in oncohematological patients after allogeneic hematopoietic stem cell transplantation (HSCT) what could help to find subjects at high risk of this type of morbidity. The main analysed factor will include the type of used posttransplant immunosuppressive prevention of GvHD, connection with haploidentical HSCT and association with BKV and AdV infection and the state of antiviral cellular immune response. Analysis of anti-viral effector T cells in HC patients with BK or AdV infection will result in determination of protective levels of anti-viral effector T cells and in characterisation of phenotype, functional activity and antigenic specificity of T cells responsible for virological and clinical response. The results of the study are essential for adoption and optimization of protocols for expansion of T cells for immunotherapy of opportunistic viral infections that endanger adult and children HSCT patients.
Phenotype and function of head and neck squamous cell carcinoma immune cells as predictive markers of clinical response
AZV 17-28055A [2017 – 2021]
RNDr. Ruth Tachezy Ph.D., PřF UK Praha
RNDr. Eva Hamšíková
The aim is to identify the prognostic factors in patients with head and neck squamous cell carcinoma ( HNSCC) to improve the predictivity of the clinical response to the available therapeutic options. A comprehensive comparative analysis of infiltrating and circulating cells of the immune system will be done in patients with HPV-associated and non-associated tumors. A specific aim of this study is to consider the role of the immunosuppressive regulatory CD4+ T cells and PD-1+CD8+ T cells and their newly identified subtypes, and the importance of the expression of the pro-angiogenic VEGF. The predictive potential of the level of expression of specific molecules in epithelial tumor cells and tumor-associated plasmacytoid dendritic cells (pDCs) will be studied. One hundred retrospective paraffin-embedded biopsy specimens and cca 150 prospective fresh biopsy tissue specimens and blood samples from HNSCC patients will be investigated by multicolor immunohistochemistry, PCR, mass cytometry, and function tests. Peripheral blood parameters of immunity will also be monitored after therapy.
Genetic variability of BKV in the Czech Republic and its influence on pathogenesis of infection in kidney transplant recipients
AZV 17-29992A [2017 – 2021]
RNDr. Martina Saláková Ph.D., PřF UK Praha
MUDr. Mariana Wohlfahrtová Ph.D., IKEM Praha, RNDr. Viera Ludvíková, MUDr. Miroslav Fajtr, FN Hradec Králové
Eighty percent of adult population is infected with BK polyomavirus (BKV). After primary infection which usually occurs in childhood, virus establish lifelong persistency in kidney with occasional reactivation. While in immunocompetent subject the infection or reactivation is clinically inapparent, in immunocompromised patients may cause severe complications. Reactivation BKV is observed in about 30% kidney transplant recipients, uncontrolled infection may lead to polyomavirus nephropathy (PVAN) and loss of graft. The factors affecting progression of infection are not yet well understood. The aim of this study is evaluate the genetic variation of BKV, as well as prevalence of various BKV genotypes and the type-specific antibodies in kidney donors and recipients and clarify risk factors for the progression of BKV infection and for the development of PVAN.
A promotor methylation of TSGs associated with HPV-driven carcinogenesis as a screening tool for anal carcinoma at risk population - validation study
AZV 17-31777A [2017 – 2021]
RNDr Jana Kašpírková PhD., LF Plzeň, UK Praha
1. Spoluřešitel: RNDr. Jana Šmahelová, 2. Spoluřešitel: Prof. MUDr. Jana Hercogová, CSc., Nemocnice Na Bulovce, Praha
Anal cancer is one of the malignancies with the rising incidence, especially at specific populations of men who have sex with men (MSM) and HIV positive patients. In these groups incidence reaches up 131 cases per 100 thousand inhabitants. Due to steeply increasing number of HIV positive patients in the Czech Republic (CR), whose vast majority belongs to MSM, early diagnosis of precancerous lesions is an essential prerequisite in the fight against this disease. Anal cancer is in its etiology and biological behavior very similar to cervical cancer, therefore the investigative and screening procedures are virtually identical. Currently used cytology in the anal area is not among the highly sensitive nor specific methods of investigation. DNA methylation appears to be a new method having already confirmed efficiency in screening of cervical cancer. This research should therefore validate DNA methylation as a potential new diagnostic and screening method for anal cancer and compare its sensitivity and specificity with established screening methods in immunocompetent and immunosuppress...
Critical evaluation of the lipidome in acute coronary syndrome and acute stroke patients in correlation with the level of oxidative stress
AZV 18-08-00149 [2018 – 2021]
Do. MUDr. Martin Malý, Ph.D.. ÚVN Praha
prof. Ing. Jana Hajšlová, CSc., VŠCHT Praha, Ing. Jiří Suttnar, CSc.
Atherosclerosis and thrombosis are underlying causes of acute coronary syndrome and stroke. In clinical practice, several markers (such as LDL, HDL cholesterol, glycaemia, C-reactive protein etc.) of elevated risk are available, however, translation of the population risk to personal risk is rather questionable. For this reason, additional information to explain such condition is of a great interest. Advanced instrumental technique represented by high performance liquid chromatography coupled to high-resolution tandem mass spectrometry will enable, based on chemometric assessment fingerprints of metabolome components, to identify the differences between patients´ groups that are not evident when employing conventionally measured parameters. Blood samples will be obtained from patients with acute and subacute phase of acute coronary syndrome and stroke. The relationship between the generated data and the degree of oxidative stress will be searched. The possibly detected changes may represent the interface between the atherosclerosis and thrombosis.
Advanced Immunomonitoring and Immunotherapy of Hematological and Hemato-oncological Patients
OP VVV CZ.02.1.01/0.0/0.0/16_025/0007428 [2018 – 2022]
The development of diagnostic methods for determination of immunosuppressive escape mechanisms of leukemic cells, that should serve for the selection of a appropriate personalized immunotherapy of hemato- oncological patients, Development of procedures for the expansion of T-lymphocytes capable of recognizing antigens of leukemic cells in AML patients, Implementation of methods for monitoring the immune system reconstitution of patients after HSCT for identification of patients with insufficient immune system reconstitution. Identification of markers predicting the longterm in vivo persistence of transferred multi-virus specific T-lymphocytes and their tracking in treated patients, the construction of a new generation of CAR T-lymphocytes.
