Grant Projects (ongoing in the year 2021)
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.
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
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
Circular RNAs and their relation to RNA splicing in the pathogenesis of myelodysplastic syndromes
20-19162S [2020 – 2022]
Ing. Michaela Dostálová Merkerová, Ph.D.
Doc. Ing. Jiří Kléma, Ph.D., FEL ČVUT Praha
Mutations in RNA splicing factors represent the most common molecular alterations in myelodysplastic syndromes (MDS). Despite some advances in the understanding of their roles in MDS pathogenesis, the impact of mutated splicing factors on circular RNAs (circRNAs) has not been studied. CircRNAs constitute a class of RNAs with a covalently closed continuous loop that has recently been discovered to be widespread and abundant. Because most circRNAs are produced by backsplicing, we hypothesize that the aberrant splicing seen in MDS also affects circRNA formation. With respect to the various regulatory functions of circRNAs, their deregulation likely contributes to MDS pathogenesis. Moreover, altered levels of particular circRNAs might serve as new molecular biomarkers for the prognosis and therapeutic response in MDS management. Moreover, circRNAs might form a new class of molecular targets for MDS treatment. In this project, we will use next generation sequencing and perform integrative data analyses and functional studies to identify and characterize circRNA roles in MDS pathogenesis.
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.
Study of molecular pathogenesis of bone marrow failure and identification of clinically relevant biomarkers in hypoplastic myelodysplastic syndrome and acquired aplastic anemia
AZV NU21-03-00565 [2021 – 2024]
Hypoplastic myelodysplastic syndrome (hMDS) and acquired aplastic anemia (AA) are severe hematopoietic disorders whose clinicopathological features overlap that makes diagnosis complicated. In both disorders, bone marrow (BM) failure occurs due to damage to hematopoietic cells by cytotoxic T-lymphocytes. However, the molecular mechanisms involved in this process are still unclear. In this context, a comprehensive genome analysis in hMDS and AA will be performed in the proposed project to characterize the molecular basis of BM failure and to define clinically relevant biomarkers for easier differential diagnosis, prediction of disease progression, and evaluation of the effect of immunosuppressive therapy on pathological clone evolution. Whole-exome sequencing will be used for characterization of genomic landscape, the transcriptome will be analyzed by RNASeq at the level of CD34+ BM cells and CD3+ lymphocytes, and mRNA and lnRNA expression profiles will be determined. Due to the etiology of the diseases, we will focus on the factors mediating the immune response and the T-cell population that will be studied in detail by flow cytometry. Knowledge of the molecular background of hMDS/AA will provide us an understanding of the disease development and will also enable to define new biomarkers which may strengthen the personalized approach to 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.
Pre-clinical validation of cGMP production of CAR T-cells for solid tumorstherapy
AZV 19-08-00147 [2019 – 2022]
Doc. RNDr. Irena Krontorád Koutná, Ph..D., FNUSA Brno
doc.MUDr. Pavel Otáhal, Ph.D., Mgr. Pavel Šimara, Ph.D., MU Brno
Chimeric antigen receptor (CAR) T-cell is a cutting edge technology for targeted cell therapy of oncologic diseases. Promising clinical results were reported for hematological malignancies, but the results in solid tumors are not that encouranging yet. Here we propose to validate protocols for the production of CAR T-cells against solid tumor antigens under cGMP rules. We will focus mainly on target antigens GD2, PSMA, and PSCA. Standard operation protocols and analytical certificates will be presented to the State Institute for Drug Control for their approval. The consortium of three prominent research facilities will participate on this project: (i) International Clinical Research Center of St. Anne's University Hospital Brno (FNUSA-ICRC), (ii) Centre for Biomedical Image Analysis at Masaryk University Brno (MU-CBIA), and (iii) Institute of Hematology and Blood Transfusion in Prague (UHKT). Our main aim is to establish production of CAR T-cells for anti-solid tumor therapy which can be translated into clinical applications.
Advanced plasmonic biosensors: towards the next-generation biomolecular interaction analysis
GA ČR 19-02739S [2019 – 2021]
doc. Ing. Jiří Homola, CSc., DSc., Ústav fotoniky a elektroniky AV ČR
Prof. Ing. Jan Dyr, DrSc., doc. Ing. Mgr. Bc. Roman Kotlín, Ph.D. MHA, Ing. Tomáš Riedel, Ph.D., Ústav makromolekulární chemie AV ČR
Life is associated with myriad of interactions that occur among a large variety of biomolecules. Hence, the understanding of biomolecular interactions and their roles in diseases represents a research goal of paramount importance. This project aims to develop a new plasmonic biosensor-based technology that will enable investigation of biomolecular interactions in complex real-world biological environments, which will advance the field of biomolecular interaction analysis beyond the current state of the art. This multidisciplinary project encompasses research efforts in multiple areas, including plasmonic (nano)structure-based biosensors, mass transport in microfluidic systems, immobilization of biomolecules, and methodologies for investigation of biomolecular interactions. The resulting biosensor technology will provide new insights into interaction of biomolecules involved in onco-hematological diseases, such as myelodysplastic syndrome and other frequently occurring hematological malignancies.
Role of nucleophosmin interactome in acute myeloid leukemia with mutated NPM
GA ČR 19-04099S [2019 – 2021]
Prof. RNDr. Petr Heřman, CSc., MFF UK Praha
Mgr. Barbora Brodská, Ph.D.
One third of acute myeloid leukemia (AML) occurrences exhibits characteristic nucleophosmin (NPM) mutation causing its aberrant cytoplasmic localization. Subsequently, multiple NPM-interaction partners, interacting also with mutated NPM or its complexes, become mislocalized from their site-of-action with functional and regulatory consequences. By combination of spectroscopic, microscopic, biochemical and immunochemical methods (e.g. FLIM, FRET, GFP-Trap) we will evaluate unknown/neglected relations between AML-related NPM mutations, oligomerization, and ability of wild-type and mutated NPM to interact with the tumor suppressor p53. Dynamics and cellular trafficking of NPM and p53 will be assessed in vivo and the role of NPM-interacting proteins regulated by p53 in the leukemogenesis will be elucidated. We will characterize cellular response of the NPM interaction network to anticancer drug treatment in relation to the NPM mutation and the drug used. Results will contribute to understanding of the role of NPM mutation in leukemogenesis and will open new strategies for AML treatment.
Blood plasma individual variability and pathophysiology and their influence on the interactions with synthetic antifouling surfaces
GA ČR 20-10845S [2020 – 2022]
Prof. Ing. Tomáš Riedel, Ph.D., Ústav makromolekulární chemie AV ČR
Ing. Pavel Májek, Ph.D.
Early biomarker detection improves treatment outcomes, survival and quality of life. In particular optical biosensors are promising technology for early diagnostics: minimally invasive procedures (plasma, saliva), rapid and sensitive detection, low sample consumption. The main pitfall of optical biosensors is the inability to differentiate a specific signal from an interfering signal caused by adsorption of particularly proteins during the contact of artificial surfaces with biological media (fouling). Fouling can result in complement or coagulation initiation, etc. It has prevented the advance of biosensors into clinical applications. In principle, fouling is influenced by individual biological variability and pathophysiology – with a few exceptions, these factors and their influence are unknown although they play a key role in clinical applicability. The aim of this project is to identify these factors and their effects, and to design sample pre-treatments to minimize or eliminate these factors.
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.
Spectrum of NGS detected somatic mutations and their association with prognosis and outcome of adolescent and young adult patients with Ph-positive leukemias
AZV NU21-07-00225 [2021 – 2024]
doc. Mgr. Kateřina Machová Poláková, Ph.D.
Prof. MUDr. Jan Trka,, Ph.D., Fakultní nemocnice v Motole, Praha
Adolescent and young adult (AYA) patients with Ph+ leukemias comprise a unique subgroup of patients with hematologic malignancies. The disease demands the careful monitoring and good compliance. Up to now, except for few clinical trials, the specific aspects and biology of Ph+ leukemias of AYA patients have not been studied in detail. Currently, most patients with chronic myeloid leukemia in chronic phase (CML-CP) have a normal life expectancy. Before tyrosine kinase inhibitors (TKIs) introduction into the clinical practice, the higher age was a negative prognostic factor. In the current era of TKIs it seems that younger patients with CML-CP at age 15-39, defined by National Comprehensive Cancer Network Guidelines as AYAs, have worse prognosis and response to TKIs. In recent years, somatic mutations in hematologic malignancies are of importance and have been highly reported. However, very little is known about the genomic landscape of somatic mutations outside the oncogene BCR-ABL1 in Ph positive leukemias - CML and Ph positive acute lymphoblastic leukemia (Ph+ALL) - of AYAs and their relation to the resistance to TKI treatment and relapses. We expect that the complex NGS-based screening of somatic mutations proposed in this project will allow us to determine whether the clonal hematopoiesis represents a worse prognostic factor for AYA patients with Ph+ leukemias. We anticipate that the similar spectrum of mutations can be identified in CML and Ph+ALL AYA patients, but with different patterns of clonal evolution in association with the different treatment protocols. This project may identify high risk AYA CML patients, who may profit from more intensive treatment protocol, similar to protocol of the Ph+ALL.
Role of transposable elements and PIWI-interacting RNAs in myelodysplastic syndrome and their potential clinical applications
AZV NU20-03-00412 [2020 – 2024]
Ing. Michaela Dostálová Merkerová, Ph.D.
Doc. Ing. Jiří Kléma, Ph.D., FEL ČVUT Praha
Myelodysplastic syndrome (MDS) is a malignant hematopoietic disorder characterized by aberrant differentiation of hematopoietic stem cells (HSCs). Genome instability is one of the key features of MDS HSCs and mobilization of transposable elements (TEs) is a known destabilizing factor of the genome integrity. PIWI-interacting RNAs (piRNAs) inhibit TE mobilization, functioning as central players in stem cell mechanisms to preserve genome integrity. Despite recent advances in the understanding of MDS pathogenesis, the role of TEs and piRNAs in development and progression of the disease has not been studied yet. We will analyze transcription of TEs and piRNAs by next generation sequencing and examine their activity in MDS. Besides the implication in the MDS pathogenesis, utilization of TEs and piRNAs as potential molecular markers of the disease progression will be tested. Moreover, possible effect of azacitidine treatment on TE and piRNA transcriptions will be addressed to prove their applicability as novel predictive markers for the drug responsiveness and relapse prevention.