2 places in full-time study

2 places in full-time study

1 place in full-time study

2 places in full-time study

2 places in full-time study

1 place in full-time study

1 place in full-time study

1 place in full-time study

3 places in full-time or combined form of study

2 places in full-time study

2 places in full-time study

1 place in full-time study

1 place in the face-to-face form of study

3 places in full-time study

3 places in full-time or combined form of study

1 place in full-time or combined form of study

Data with clumping at a single value commonly occur in biometrics. Typically, the outcome variable measures an amount that must be non-negative and may in some cases be zero. Semicontinuous data can be viewed as arising from two distinct stochastic processes: one governing the occurrence of zeros and the second determining the observed value condition being a non‐zero response. The aim of the thesis is to describe and compare methods of analyzing semicontinuous data with regards to the application on statistical problems solved at IMTM, e.g. proteomics analyses.

One of the main goals of chemoinformatics is development of new compounds with desired properties or activities. Many de novo design approaches were suggested so far. The designed compounds should satisfy multiple criteria, e.g. synthetic accessibility, novelty, diversity, selectivity, etc. Generators of chemical structures satisfying these criteria are a core of all de novo design approaches. Available approaches often result in synthetically hardly accessible structures or limit their diversity and novelty. Within this study a new fragment-based approach for structure generation will be implemented which will result in chemically valid structures and will provide flexible control over their diversity, novelty and synthetic accessibility. This will be used for development of de novo design approaches based on molecular docking, pharmacophore modeling to generate compounds which will be able to fit to a binding site of a given protein. This can be used for development of novel compounds and for optimization of structures of available ligands. Developed approaches should be implemented in open-source software tools.

Pharmacophore modeling is a powerful approach to encode possible protein-ligand interactions and searching of new promising compounds in large libraries. So far, almost all available software for pharmacophore modeling is proprietary and implemented approaches have some limitations to efficiently work with big data. Within this study a new approach to represent 3D pharmacophores as hashes will be implemented. This representation will make it possible to quickly identify similar pharmacophores in large data sets. This property can be used to develop a new alignment free approach to ligand-based pharmacophore modeling. The developed 3D pharmacophore hashes will help to identify representative pharmacophores retrieved from molecular dynamic simulation of protein-ligand complexes. These developments will increase success rates of future screening campaigns and should be implemented in open-source software.

Although hundreds of biological databases are available, a richly annotated database of anti-aging compounds with diverse mechanisms of action has been missing. The aim of the project is to create a database of compounds with anti-aging activity that would offer a rich annotation of both compound and involved biological mechanisms. The data will be collected from a wide range of public databases, by text-mining of scientific literature and patents as well as from results of in-house high-throughput screening. The data will be used for formulation of new hypotheses of mechanisms of aging as well as for identification of novel anti-aging compounds.

The study of ADME properties of a potential drug that are part of the IMTM chemical library - obtained by national or international cooperation belongs to one of the first steps in predicting potential drugs. In vitro models generate many ADME parameters, including chemical, plasma and microsomal stability, plasma protein binding and proportion of passive diffusion as a transport mechanism. The Caco-2 and MDCK-MDR1 permeability assays are established models of intestinal and blood-brain barriers, respectively. Analysis of samples is performed using a Agilent RapidFire 300 - rapid online solid phase extraction with subsequent detection of the mass spectrometer Qtrap 5500 (AB Sciex) - RF/MS. High-Throughput Mass Spectrometry System RF/MS delivers ultrafast, label – free analysis of native compounds for biochemical assays in ADME and provide throughput speeds of 6 to 10 seconds per sample.

The student will employ modern in vivo imaging techniques namely positron emission tomography, single-photon emission tomography, computed tomography and optical imaging in order to elucidate effect of novel anticancer or antimicrobial agents. The other part of the project will be assessment of novel radiotracers directed towards targets expressed by tumour cells or by microbial pathogens. Daily work routine will include all proper working steps common in radiopharmacy, i.e. starting with gaining an radioisotope from dedicated source, radiolabelling of selected compound, quality control (HPLC/TLC), stability tests, in vitro testing of biological properties and finally in vivo procedures (biodistribution, static/dynamic imaging). Expected previous education includes medicine, pharmacy, pharmacology or related field.

Hypoxia is a prominent feature of different solid tumor types. A central component of hypoxic adaptation is the stabilization of hypoxia-inducible factor-1 (HIF-1), a key transcriptional regulator of hypoxia that orchestrates the transcriptional regulation of genes involved in a plethora of cellular processes. Considering the multiple roles of HIF-1 in cancer, interest in novel small-molecule inhibitors of the HIF-1 pathway has steadily increased over the past 10 years. However, despite extensive research, no specific inhibitor of HIF-1 has been brought to the market, making the field still ripe for further exploration. The goal of the present work is to utilize the potential of a combination of 2D and 3D cellular models for identification and characterization of inhibitors of HIF-1 and/or HIF-1 pathway by screening in 2D cultures, and lightsheet microscopy and mass spectrometry studies in spheroid cultures.

Recently, we identified several novel modulators of alternative splicing with the ability to increase expression of wild-type transcripts of several genes relevant for neurodegeneration or cancer. However, mechanisms of action of those promising compounds remains unclear. The aim of the project is to (i) identify molecular targets and relevant pathways, (ii) design assays for high-througput screening of a library of chemical compounds, and (iii) to identify novel structural types of active compounds.

Pharmacotherapy of hereditary mitochondrial diseases including neurodegenerations and cardiopathies is only symptomatical at present. The aim of this study is to identify the novel candidate drugs by high-throughput screening using patient-derived cell lines. The assays will evaluate survival under metabolic and oxidative stress as well as morphology and function of mitochondria. Mechanism of action of promising compounds will be studied by OMICS methods.

The so-called double-strand breaks (DSB) are the most lethal DNA lesions, which can be potent sources of mutations and thus become the beginning of irreversible genetic changes leading to degenerative illnesses, including cancer. At the same induction of DSBs introduced in the proper setup can become an unsolvable problem for the cells, particularly in specific genetic backgrounds typical for cancer, which fact is the rationale for a plethora of cancer treatment strategies. Thus the way cells deal with DSBs is under the great interest of current medicinal and biological research. The Ph.D. student will practice several methods of induction of DSBs via various sources such as gamma rays, alpha particles, UV light and various chemical inducers. Next will be studied the molecular mechanisms the cell deal with this type of DNA damage. Emphasis will be put on differences between normal and cancer cells and their potential exploration for cancer therapy. Student will also learn mutiple laboratory techniques including cell culture, RNA/DNA transfections, advanced microscopic techniques, live-cell imaging, and various biochemical analysis of proteins.

Our DNA is constantly under threat from DNA damaging agents. If unrepaired DNA damage can lead to errors during genome duplication, including the mutations that can lead to cancer, contribute to aging and other human diseases. Cells have evolved elaborate repair mechanisms to fix this damage and ensure that the genetic information is faithfully reproduced, and we would like to understand these repair mechanisms at the molecular level. We ultimately aim for a complete molecular and cellular understanding of critical DNA repair pathways that act on DNA damage. The Ph.D. student will practice several molecular and cellular techniques, including cell culture, RNA interference, immunofluorescence microscopy, live-cell imaging and immunoprecipitation of proteins. He/she will also learn novel and powerful techniques, such as super-resolution microscopy and purification of proteins on newly synthesized DNA.

Mechanisms of tumor cell resistance to newly developed and existing nucleoside analog cytostatics will be studied. These drugs are used in most anti-cancer therapy protocols and the emergence of drug resistance is a major problem in the treatment of cancer patients. Resistant cell lines prepared in the past will be studied to identify the key mechanisms of resistance, which will be carried out by their detailed characterization using cell biology, but also proteomics and molecular genetics. The significance of the identified changes will be further verified on clinical material and will be applied in the development of new anticancer drugs from this class.

Hypoxia is one of the major factors causing resistance to microtubule-stabilizing drugs (MSDs) and other non-microtubule drugs used in chemotherapy. Hypoxia results in changes in tubulin conformation, expression of tubulin isotypes and metabolic pathways that make cancer cells less susceptible to paclitaxel, a taxane used extensively in the treatment of solid tumors. Recent cellular studies have shown that non-taxane MSDs with a similar mode of microtubule stabilization to paclitaxel is more effective in hypoxic cancer cells than paclitaxel. Due to a different microtubule-binding site, we hypothesize that non-taxane MSDs may have a better cytotoxic effect in cancer cells under hypoxia. The goal of this project is to study the anti-cancer effect of non-taxane MSDs in hypoxic ovarian and cervical cancer cell models.

Selected, highly active derivatives of triterpenes, chelators and nucleosides will be studied with a view to identify the mechanisms of their antitumor effects. Advanced methods of cell biology, proteomics and genomics such as affinity purification of protein targets, CETSA and others will be used for their study. The identified targets will be validated in relation to their clinical relevance in anticancer therapy.

High-risk human papillomavirus infection (HPV infection) is associated with several cancers such as cervical, vaginal, vulvar, head and neck, anal, and penile carcinomas. Nearly all cervical cancers are caused by HPV infection. Despite available vaccination and cervical cancer screening program, cervical cancer is one of the most common types of cancer affecting women worldwide. Main problems of cervical cancer screening are low participation rate and low sensitivity of cytology which is still used in the majority of cervical cancer screening programs. Solution could be the transition to primary HPV screening and the sending of self-sampling devices to cervical cancer screening non-attenders. The best strategy for enrolling Czech women in the screening program will be analysed during this project. Obtained samples will be tested for the presence of HPV DNA and the presence of other molecular biomarkers important in viral clearance and cervical cancer progression/regression. Discoveries will lead to identification of biomarkers for early diagnosis, disease progression or triage strategies. The aim of the project is to clarify the best strategy for enrolling women who do not attend cervical cancer screening program. The second aim is to study genetic and proteomic profile of HPV positive/negative women with normal/abnormal cervical cytology as well as genetic variants of HPV and its importance for regression/progression of the disease. Skills to be taught include biochemistry, molecular biology, bioinformatics and cell culture. This is an ideal project for a student who wishes to pursue higher studies in cancer research. The project will use various techniques including PCR, in situ hybridization, next generation sequencing, mass spectrometry.

An extensive structural and biochemical characterization of tau oligomeric species in Alzheimer’s disease and other tauopathies

Glycation is one of the endogenous aging mechanisms that occurs spontaneously with time, but also in a pathological manner during diabetes, renal failure, and inflammation. Advanced glycation end products (AGEs) are non-enzymatic modifications of proteins or lipids after exposure to sugars. The accumulation of glycated macromolecules is a hallmark of aging both in humans and experimental animals. RAGE is the best-characterized cell surface molecule that recognizes AGEs. The interaction between an AGE and its receptor alters cell and organ functions mainly through inflammatory molecules, leading to aging. RAGE regulates a number of cell processes of crucial importance such as inflammation, apoptosis, ROS signalling, proliferation, autophagy, and aging. RAGE thus represents potential for research and development of diagnostic and therapeutic strategies. Although there were several small molecular RAGE inhibitors described in the literature, they mostly have not shown proof-of-concept therapeutic potential, and thus, there is still potential for future developments in the field. This topic will be focused on the investigation of compounds from IMTM chemical library as potential inhibitors of RAGE receptor.

The aim of the project is to identify the novel compounds which can increase life-span of C. elegans, increase their resistance against stress and neurodegeneration, using high-throughput and high-content screening platforms. Active compounds will be further studied in human cell cultures. Mechanisms of action of interesting hits will be studied by OMICS

One of the targets in the search for prognostic and predictive biomarkers in oncology is genetic and cytogenetic changes that can control or influence cell proliferation and differentiation. These changes may be tumor-specific or occur across different proportions of different malignancies. The aim of this work will be to identify and describe known or less known genetic markers and to consider their suitability for routine testing also in other diagnoses.

Ph.D. topic is focused on the identification of biomarkers of lung diseases by means of a non-invasive collection of exhaled breath condensate. The project will monitor the presence of proteins in exhaled air in various diseases such as asthma, cystic fibrosis, lung tumors, or some infectious diseases, as well as quantitative changes of these proteins compared to a healthy population. Changes in these potential biomarkers with respect to therapeutic response and disease progression will be evaluated and validated.

Clonal hematopoiesis of indeterminate potential (CHIP) has recently been described as a common phenomenon associated with aging. It is characterized by the accumulation of somatic mutations in cells of the hematopoietic system. Although CHIP is manifested by the expansion of certain cell clones, this condition is not accompanied by any morphological features of hematological neoplasia. However, it has been shown that the incidence of clonal hematopoiesis correlates with increased overall mortality and the risk of developing malignant transformation of hematopoietic cells as well as cardiovascular disease, such as ischemic stroke. To what extent and by what mechanisms clonal hematopoiesis contributes to disease development remains a question of current research. The main aim of the project will be to pinpoint the principal cells carrying CHIP somatic mutations, and to study their role in development and maintenance of atherosclerotic plaques, especially of those involved in development of stroke. The comparison of the phenotype of CHIP positive and negative cells will be of special interest. The use of cellular models not only include different types of leucocytes but circulatory progenitor endothelial cells as well. The study will involve elderly subjects with the positive presence of CHIP (>65 years). Subject will be characterized based on the presence or absence of ischemic stroke and the presence or absence of carotid stenosis by our clinical collaborators. The presence of somatic variants in 38 selected genes associated with CHIP will be tested in subjects of interest within our research group. The project will use various techiques including FACS, MACS, cell cultures, DNA isolation from small amount of cells, a highly sensitive sequencing method for DNA genotyping allowing detection of variant with less than 1% allelic frequency, DNA/RNA sequencing library preparation, deep massively parallel sequencing of panel of genes using unique molecular barcodes/indices, RNAseq, bioinformatics and data analysis with possibilities of calculations using high performance computing cluster, data management and statistical evaluation.

Cancer is the second leading cause of death in the western countries. Early diagnosis and targeted therapy improve the therapeutic outcome. With the emergence of new biotechnologies, diagnosis can be made early and precisely, and the knowledge of tumor molecular genetics can identify the most appropriate therapy for a particular patient. The sensitivity of modern molecular methods makes it possible to characterize the tumor properties from sites remote from the primary tumor using patient's blood. The subject of the offered study program is the identification of new prognostic and predictive biomarkers of cancer using liquid biopsies. This is particularly the analysis of circulating tumor cells (CTCs), circulating free tumor DNA (ctDNA) and circulating miRNAs. The aim of the project is to further implement a liquid biopsy concept into the diagnosis and therapy monitoring of solid tumors, especially colorectal, breast, lung and CNS tumors. These include therapy response and resistance monitoring, identifying new therapeutic targets and estimating disease prognosis. The project will provide training in widely-used, transferable techniques, including circulation tumor cells capture system, digital droplet PCR, reverse-transcription qPCR, RNA-seq, single cell analyses, xenografts models and other multi-omics methods. We are looking for candidates with a background in Molecular Biology, Medicine, Cell Biology or a related area, who are enthusiastic about investigating novel approaches in cancer diagnostic that have significant potential for public health.

Early diagnosis and treatment are avenues to better outcomes in routine pediatric rheumatology clinical practice. Criteria for early diagnosis of systemic sclerosis or systemic lupus erythematosus have been recently approved for routine clinical practice in adult rheumatology. They represent useful tools also for pediatric patients. Students will work with pediatric rheumatology patients (i.e. systemic lupus erythematosus, systemic sclerosis, vasculitides), and will be involved in clinical assessment and laboratory data analysis, looking for clinical findings/laboratory biomarkers of early diseases, analysing potential predictors of severe disease course, including non-invasive biomarkers.

Personalized therapy in pediatric rheumatology could bring better outcomes into routine clinical practice. Students will work with pediatric rheumatology patients (i.e. juvenile idiopathic arthritis, systemic lupus erythematosus, systemic sclerosis, localized scleroderma), and will be involved in clinical assessment and laboratory data analysis, looking for response predictors, analysing potential predictors of disease activity/relapse, including non-invasive markers (i.e. HER-2 in systemic lupus erythematosus).