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Biochemie a bioorganická chemie

Biochemie a bioorganická chemie

CHYBI CHARAKTERISTIKA PROGRAMU

Cílem tohoto programu je připravit vysoce kvalifikované odborníky schopné samostatné vědecké práce, kteří se budou podílet na zavádění nových vizí a moderních postupů do praxe nebo budou pokračovat ve své vědecké činnosti na vysokých školách a vědeckých ústavech a budou tak přispívat k objasňování principů fungování živých organismů. Program Biochemie a bioorganická chemie vznikl sloučením dvou oborů chemie. Bude tak vychovávat odborníky orientované více na biochemii nebo na bioorganickou chemii. Společným jmenovatelem těchto oborů je poznávání chemické podstaty důležitých pochodů v živých organismech, studium vztahu mezi strukturou a biologickou aktivitou biopolymerů, ale i přírodních organických látek nebo jejich syntetických analog.

Careers

Absolvent tohoto programu je schopen v praxi uplatnit znalosti z různých oborů jako je biochemie, buněčná biologie a molekulární genetika, mikrobiologie, organická chemie a chemie přírodních látek (ve vazbě na téma disertační práce). Na základě získaných znalostí dokáže samostatně plánovat výzkumný projekt, kriticky hodnotit rizika navržených postupů a uplatňovat inovativní postupy ve výzkumu. Další získanou kompetencí absolventa je zkušenost s pedagogickou a manažerskou činností v rámci zapojení do výuky bakalářských a magisterských programů především v roli asistentů při laboratorních cvičeních a při konzultacích bakalářských a diplomových prací. Teoretické, experimentální, pedagogické a manažerské zkušenosti absolventy předurčují k tvůrčí vědecko-výzkumné činnosti, která je stále více žádána na nejrůznějších pracovištích ústavů akademie věd ČR, vysokých škol, zdravotnických zařízení, farmaceutických firem a státních i soukromých výzkumných laboratoří v ČR i v zahraničí, které se zabývají problematikou z oblasti biochemie a bioorganické chemie.

Programme Details

Language of instruction Czech
Standard length of study 4 years
Form of study Full time + Combined
Guarantor of study programme doc. Ing. Petra Lipovová, Ph.D.
Programme Code D304
Place of study Praha
Capacity 35 students
Number of available PhD theses 40

List of available PhD theses

3D superresolution microscopy for accessing mitochondrial ultramorphology

Department: Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology
Also available in programme: Biochemistry and Bioorganic Chemistry
Theses supervisor: RNDr. Petr Ježek, CSc.

Annotation

3D nanoscopy has not yet assessed mitochondrial cristae morphology, nor the internal structure of mitochondrial DNA (mtDNA) & protein complexes, termed nucleoids. Hence, we’ll survey 3D-redistribution of cristae and their shaping proteins or nucleois employing our prototype Vutara 3D superresolution microscope for stochastic techniques such a PALM and dSTORM. We will conduct studies under physiological situations vs. pathology (type-2 diabetes, cancer) using dSTORM with nanobodies or FRET excited PALM/dSTORM. Thus nm changes will be reflected by novel 3D nanoscopy methods. Also mtDNA nucleoids will be studied at increased and diminished mitochondrial biogenesis, while applying own mitoFISH nanoscopy for D-loop counting. Artificial manipulations of nucleoid size and mtDNA content will be studied as well as nucleoid division. Results will be translated into specific protocols for 3D nanoscopy, specifically developing novel relevant 3D image analyses based upon the Ripley’s K-function and Delaunay algorithm. Molecular cell biology will thus be combined with up-to-date 3D nanoscopy. Note, the molecular biology techniques will be conducted and be ready for the applicants by the coworkers of the Department No.75.

Anammox bacteria and their unique phospholipids

Department: Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology

Annotation

Anammox (anaerobic ammonium oxidation) bacteria, which were discovered relatively recently, play an important role in the global nitrogen cycle, thanks to their unique metabolism, the conversion of ammonium cation (NH4+) and nitrite (NO2-) to nitrogen. In this way, up to 50 % of ocean nitrogen is produced in oxygen-restricted zones. Currently, these microorganisms are used in wastewater treatment as ideal substitutes for the denitrification process. The sequence of reactions of anammox metabolism takes place on the membrane of a special compartment inside these bacteria called the anammoxosome. All membranes of anammox bacteria, including the anammoxosome, are composed of unique ladderan lipids. These are phospholipids which contained 5 cyclobutanes or a combination of 3 cyclobutanes with cyclohexane at the end of the acyl chain. Thanks to these unique lipids, the membrane of the anammoxosome transmits protons up to ten times slower than the classical bilayer of phospholipids, which helps maintain the proton-motive power of these bacteria. Not much is known about the synthesis of these special phospholipids. The aim of this work will be to contribute to the detection of enzymes involved in the synthesis and degradation of these phospholipids in anammox bacteria.

Approaches to the Total Synthesis of Fumiquinazoline-Based Pyrazinoquinazoline Alkaloids and Analogs

Department: Department of Chemistry of Natural Compounds, Faculty of Food and Biochemical Technology
Also available in programme: Biochemistry and Bioorganic Chemistry
Theses supervisor: Dr. habil. Ullrich Jahn

Annotation

In this project, short and bioinspired synthetic approaches to complex fumiquinazoline-based pyrazinoquinazoline alkaloids will be developed. The total syntheses will be modular and aimed at investigating their biological profiles in collaboration. Small focussed libraries of analogs are envisaged to complement the total syntheses of the natural products.

Approaches to the Total Synthesis of Glyantrypine-Based Pyrazinoquinazoline Alkaloids and Analogs

Department: Department of Chemistry of Natural Compounds, Faculty of Food and Biochemical Technology
Also available in programme: Biochemistry and Bioorganic Chemistry
Theses supervisor: Dr. habil. Ullrich Jahn

Annotation

In this project, short and bioinspired synthetic approaches to complex glyantrypine-based pyrazinoquinazoline alkaloids will be developed. The total syntheses will be modular and aimed at investigating their unknown biological profiles in collaboration. Small focussed libraries of analogs are envisaged to complement the total syntheses of the natural products.

Biocatalysts for a new route of nitrile synthesis

Department: Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology
Theses supervisor: Ing. Ludmila Martínková, DSc.

Annotation

Nitriles (R-CN) are currently used for the synthesis of fine and pharmaceutical chemicals. The benefits of enzymatic synthesis in general are mild conditions and selectivity. Aldoxime dehydratase, an enzyme enabling the synthesis of nitriles, occurs in bacteria and fungi. However, the enzyme is difficult to obtain directly from these organisms due to its low production. Therefore, the strategy will be to retrieve the genes from databases, have them commercially synthesized and express them in a heterologous producer, primarily Escherichia coli. This is expected to allow production of sufficient amounts of the enzymes for catalysis. The thesis will be a part of a Czech-Austrian project aiming to elaborate a new cascade synthesis of nitriles. Aldoxime dehydratase catalyzes the last step of the cascade consisting of 1) enzymatic preparation of aldehyde from carboxylic acid, 2) conversion of aldehyde into aldoxime (R-CH=NOH) and 3) dehydration of aldoxime into nitrile. The thesis is multidisciplinary, using methods of molecular biology, bioinformatics, biochemistry, biotechnology and organic chemistry.

Cathepsin proteases in biomedicine

Department: Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology
Also available in programme: Biochemistry and Bioorganic Chemistry
Theses supervisor: RNDr. Michael Mareš, CSc.

Annotation

The project is focused on proteolytic enzymes of the cathepsin type that are critically involved in pathologies and are therapeutic targets. Cathepsins of human origin and those from pathogens and parasites will be investigated. The aim of the project is to analyze the structure and function of cathepsins and develop novel inhibitory molecules for their regulation. The research in the field of biochemistry and molecular biology employs the following main approaches: functional proteomics and chemical genomics, recombinant protein expression, enzymology, protein crystallography, and molecular modeling

Characterization of early postnatal development using a biobank of tissues of human newborns

Department: Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology
Theses supervisor: MUDr. Jan Kopecký, DrSc.

Annotation

Early postnatal period is critical with respect to development of the key physiological functions and homeostatic mechanism of the newborn, as well as for imprinting the metabolic features that could be manifested during the adolescence and adulthood. A unique biobank of the autopsy samples of various is available that had been collected from human newborns, mostly very premature newbors. Characterization of the transcriptome of the tissues using RNA sequencing analysis is ongoing.
The project will focus on tah data analysis in order to reveal various aspects of early human development and its control, also with regards to various pathologies. Model experiments on mice will reperesent the main experimental part of the project. It will proceed in close collaboration between the Department of Adipose Tissue Biology and the Department of Metabolomics of the Institute of Physiology of the Czech Academy of Sciences (http://www.fgu.cas.cz/en/departments/adipose-tissue-biology), and the Institute for Inherited Metabolic Disorders, First Faculty of Medicine, Charles University (http://udmp.If1.cuni.cz/en/genomics-and-bioinformatics-laboratory) in Prague. This multidisciplinary environment will be key for the appropriate tarining of the student and successful work on the projekt. The basic PhD scholarship will be supported by the employement at the Department.

Comprehensive approach to structural analysis of novel polycyclic diterpenes from termites

Department: Department of Chemistry of Natural Compounds, Faculty of Food and Biochemical Technology
Also available in programme: Biochemistry and Bioorganic Chemistry
Theses supervisor: Mgr. Pavlína Kyjaková, PhD.

Annotation

Termites are the group of insects with the richest repertoire of defensive chemicals. They are especially famous for the production of roughly one hundred different polycyclic diterpenes with variable topologies of double bonds combined with different oxygenated moieties attached to bi-, tri- and tetracyclic diterpene skeletons. In spite of the extensive quest for new termite diterpenes during the past decades, large part of their structural richness remains undiscovered. The proposed PhD. project focuses on chemical diversity of polycyclic diterpenes in the so-called Subulitermes group of species from South America, in which we recently unveiled an unexpected repertoire of diterpenes structures. The project will address the diterpene diversity as a tool for chemical taxonomy on the one hand, and an opportunity to fully identify structures of new and complex natural compounds on the other hand. The first goal will be to characterize individual species based on combination of characteristic chemical profiles with mitochondrial DNA sequences, to identify new species, to discriminate cryptic species, and ultimately to build phylogenetic hypotheses on their relationships. The knowledge on the overall diterpene diversity will serve as a basis for the second goal of the project, which will combine traditional analytical workflow with modern approaches and computational tools to fully characterize the molecular structures in a maximum of detected diterpenes.

Crystalline sponge method

Department: Department of Chemistry of Natural Compounds, Faculty of Food and Biochemical Technology
Also available in programme: Biochemistry and Bioorganic Chemistry
Theses supervisor: Ing. Tomáš Pluskal, Ph.D.

Annotation

Our lab combines cutting-edge experimental (e.g., LC-MS, metabolomics, RNA-seq) and computational (e.g., bioinformatics, molecular networking, machine learning) approaches to develop rapid, generally applicable workflows for the discovery and utilization of bioactive molecules derived from plants. We are looking for talented and motivated chemist with a strong experience in small molecule X-ray crystallography. The successful candidate for this position will be developing protocols for the “crystalline sponge” structure elucidation method and applying them to various plant natural products, particularly terpenes.

Design and synthesis of inhibitors of purine nucleoside phosphorylases – SAR study

Department: Department of Chemistry of Natural Compounds, Faculty of Food and Biochemical Technology
Also available in programme: Biochemistry and Bioorganic Chemistry
Theses supervisor: Ing. Zlatko Janeba, Ph.D.

Annotation

We have recently prepared a novel type of acyclic nucleoside phosphonates as potent inhibitors of human purine nucleoside phosphorylase (hPNP). Such compounds may have potential to treat various T-cell leukemias. In order to select suitable candidates for preclinical evaluation, the goal is design and synthesis of a larger amount of derivatives and evaluation of their biological properties. The synthesis of potential PNP inhibitors will be developed and optimized.

Design and synthesis of novel photoswitches derived from heteroarylazobenzenes and bis-azobenzenes

Department: Department of Chemistry of Natural Compounds, Faculty of Food and Biochemical Technology
Also available in programme: Biochemistry and Bioorganic Chemistry
Theses supervisor: Ing. Zlatko Janeba, Ph.D.

Annotation

We have recently reported synthesis of variously substituted 5-phenylazopyrimidines (see references for more information). Their physicochemical properties were studied using in situ irradiation NMR spectroscopy and optical spectroscopy. The goal of the current project will be synthesis of novel molecular photoswitches based on a combination of bis-azobenzenes and pyrimidines (and other heterocycles), namely bis(pyrimidinyldiazenyl)benzenes. Their synthesis will be developed/optimized and their physicochemical properties will be studied.

Design and synthesis of novel prodrugs of acyclic nucleoside phosphonates

Department: Department of Chemistry of Natural Compounds, Faculty of Food and Biochemical Technology
Also available in programme: Biochemistry and Bioorganic Chemistry
Theses supervisor: Ing. Zlatko Janeba, Ph.D.

Annotation

Acyclic nucleoside phosphonates (ANPs) represent an important class of antiviral agents. The phosphonate group is deprotonated at physiological pH and, thus, ANPs are polar molecules unable to effectively penetrate into cells. Prodrugs of ANPs help to overcome this obstacle. The goal of the project will be design and synthesis of novel prodrugs of ANPs and study of their properties.

Development of new chemical tools to study cell-cell interactions

Department: Department of Chemistry of Natural Compounds, Faculty of Food and Biochemical Technology
Also available in programme: Biochemistry and Bioorganic Chemistry
Theses supervisor: Ing. Milan Vrábel, Ph.D.

Annotation

Cell-cell interactions play an important role in a myriad of biological processes. These interactions enable cells to communicate, respond to changes in the environment and are involved in many pathologies including cancer. Despite their importance, our ability to study the molecular details and nature of these interactions is still very limited. In this project, we will employ chemical glycoengineering in combination with biocompatible chemical crosslinking reactions to capture, identify and study biomolecules involved in these interactions. This project aims to elucidate the complexity of cell-cell interactions and shed light on individual proteins involved in the process. The ideal candidate should have interest in organic chemistry, chemical biology and related fields.

Fish identification: molecular-biological and proteomic approaches

Department: Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology

Annotation

Food market is still broadened with new products from different producers and suppliers, which increases the diversity of consumers' menus on one hand, but therewithal it creates conditions for food fraud on the other hand. Food fraud may be associated also with health hazards for consumers. The consumers´ misleading can be done e.g. by replacing more expensive raw materials with cheaper ones, failing in complying the declared composition or by deliberately mislabelling the geographical origin or the production method. One category of often-falsified food are fish, fish products and seafood, which are also associated with the occurrence of significant allergens. The work aims to develop and experimentally verify methodologies for the identification of fish using DNA and protein analysis. Molecular-biological methods should allow such species determination within the class of Actinopterygii, and will comprise modern methods such as polymerase chain reaction (PCR, qPCR, and dPCR) and sequencing. The target gene to be analysed is the gene encoding the main fish allergen, parvalbumin. The proteins analysis will be aimed at comparing proteins profiles obtained by mass spectrometry MALDI-TOF.

Identification of new psychoplastogenic compounds through structure-activity relationship studies as potential neurochemical tools for investigating human cognition

Department: Department of Chemistry of Natural Compounds, Faculty of Food and Biochemical Technology
Theses supervisor: doc. Ing. Martin Kuchař, Ph.D.

Annotation

Objectives of this research project are to discover and synthetize novel chemical compounds with potential psychoplastogenic properties to be used as tools for neuroimaging studies elucidating their underlying neurobiological mechanisms. Using structure-activity relationship investigations of already known and described psychoactive compounds primarily of the tryptamine and phenethylamine classes, this project aims to design and develop synthetic routes for their new analogues and to identify suitable substances for pharmacological and neurobiological investigations. Their biological activity will be tested within international collaboration for their interaction with monoamine receptors and transporters, cytotoxicity, and effects on growth of neuronal cells (by monitoring the BDNF factor). Selected compounds will be subjected to preclinical studies in animal models, especially with the use of behavioral tests and imaging methods such as EEG, fMRI and in the case of isotopically labeled substances also with PET.

Isolation of novel therapeutics form fungi

Department: Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology
Theses supervisor: prof. Ing. Pavel Kotrba, Ph.D.

Annotation

Fungi have been always on the forefront of biotechnological research, be it for antibiotics, food production, various enzymatic mixtures etc. Yet, there is still an untapped potential with regards to therapeutic use against cancer or various psychological disorders, although there are reports of fungi being traditionally used for such purposes. This dissertation project is aimed on the identification and isolation of novel therapeutics from common forest fungi such as Amanita muscaria and testing of the therapeutic potential of the isolated substances in various types of cancer cell lines.

Light upconversion nanoparticles for infra red photodynamic therapy of tumors

Department: Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology
Also available in programme: Biochemistry and Bioorganic Chemistry
Theses supervisor: RNDr. Petr Ježek, CSc.

Annotation

For numerous tumor types resistance to long-term monotherapies usually develops. In order to overcome it, we shall develop and photophysically test nanoparticle-based systems for infra red photodynamic therapy. Threrefore, we will study detailes photophysics of nanoparticles, namely luminescence kinetics for upcovversion nanoparticles NaY(Gd)F4:Yb3+(Nd3+)/Er3+(Tm3+), which convert either 980? 650/540 nm or 808?650 nm. All these studies will be conducted in the absence and in the presence of a photosenzitizer in the nanoparticle shell, which creates singlet oxygen upon the desired excitation. The second imaging mode will be enabled for cracking these nanoparticles by NMR or PET. Particle surface engineering will include coating with polymers to achieve the highest energy transfer, immobilization a photosenzitizer to induce optimal singlet oxygen formation, and attachment of addressing peptides to facilitate cell internalization. Chelator for 64Cu or 125I attachment will be also introduced to integrate upconversion luminescence with PET imaging. Singlet oxygen production and pharmacokinetics of the particles on nude mice with xenotransplanted tumors will be also determined. The molecular biology techniques will be conducted by the coworkers of the Department No.75., Inst. Physiology.

Liquid chromatography–mass spectrometry for metabolomics and lipidomics studies

Department: Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology
Also available in programme: Biochemistry and Bioorganic Chemistry
Theses supervisor: doc. Ing. Tomáš Čajka, Ph.D.

Annotation

Over the last decade, mass spectrometry-based metabolomics and lipidomics have become key disciplines for the comprehensive profiling of polar metabolites and complex lipids in biological systems. Liquid chromatography–mass spectrometry (LC–MS) is the preferred technique in metabolomics and lipidomics permitting effective compound separations and detection. However, there is still a lack of sufficient data on the metabolome and lipidome characterizing biofluids (i.e., plasma, serum, urine) and tissues, which can be easily accessible and reused at any time for future studies. The PhD project aims to focus on (i) merging targeted and untargeted metabolomics and lipidomics methods, (ii) standardization of methods, and (iii) extending the breadth and scope of methods for metabolomics and lipidomics studies (e.g., type 2 diabetes, circadian rhythms). The work will be conducted at the Institute of Physiology CAS and financially supported by various grants (GACR, MSMT, AZV).

Mass spectrometry-based metabolomics of biological systems

Department: Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology
Theses supervisor: doc. Ing. Tomáš Čajka, Ph.D.

Annotation

Untargeted metabolomics methods focus on the analysis of all the detectable metabolites in a sample, including chemical unknowns. Liquid chromatography coupled to mass spectrometry (LC-MS) is the preferred technique in metabolomics permitting effective compound separations and detection. However, up to 80% of all detected signals from untargeted profiling represent unknown metabolites. Such a big obstacle in biomedical and biological research hinders meaningful biochemical and pathway interpretations. The PhD project aims to focus on (i) increasing the coverage of spectral libraries used for metabolite annotation, (ii) applying programs for the prediction of ‘unknown’ metabolites, and (iii) using bioinformatics tools for visualization and interpretation of the data obtained within metabolomics studies (e.g., type 2 diabetes, circadian rhythms). The work will be conducted at the Institute of Physiology CAS and financially supported by various grants (GACR, MSMT, AZV).

Mass spectrometry-based metabolomics of biological systems

Department: Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology
Theses supervisor: doc. Ing. Tomáš Čajka, Ph.D.

Annotation

Untargeted metabolomics methods focus on the analysis of all the detectable metabolites in a sample, including chemical unknowns. Liquid chromatography coupled to mass spectrometry (LC-MS) is the preferred technique in metabolomics permitting effective compound separations and detection. However, up to 80% of all detected signals from untargeted profiling represent unknown metabolites. Such a big obstacle in biomedical and biological research hinders meaningful biochemical and pathway interpretations. The PhD project aims to focus on (i) increasing the coverage of spectral libraries used for metabolite annotation, (ii) applying programs for the prediction of ‘unknown’ metabolites, and (iii) using bioinformatics tools for visualization and interpretation of the data obtained within metabolomics studies (e.g., type 2 diabetes, circadian rhythms). The work will be conducted at the Institute of Physiology CAS and financially supported by various grants (GACR, MSMT, AZV).

Modified DNAzymes and DNA origami

Department: Department of Chemistry of Natural Compounds, Faculty of Food and Biochemical Technology
Also available in programme: Biochemistry and Bioorganic Chemistry
Theses supervisor: prof. Ing. Michal Hocek, DSc.

Annotation

We will design and synthesize modified deoxyribonucleoside triphosphates bearing functional groups or ligands for complexation of metals. They will be used for enzymatic synthesis of modified oligonucleotides which will be applied in selection and construction of functional DNAzymes or DNA origami.

Molecular characterization of various variants of fish parvalbumin gene in respect of biochemical and allergenic features of corresponding expressed proteins

Department: Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology

Annotation

Fish parvalbumin gene is composed of four exons separated by three introns. The gene encodes highly thermoresistant parvalbumin protein. This protein can act as food allergen in predisposed consumers. Intron sequences of the gene can due to their uniqueness serve as species determination marker, while exons encode protein, including respective epitopes triggering allergic reaction. In each fish species, parvalbumin gene is represented by number of paralogs. The aim of the dissertation is to characterize these paralog/ortholog variants by means of molecular tools as well as by biochemical and immunochemical approaches, building on phylogenetic data obtained from databases as well as from NGS. Obtained dataset should also serve as a base for next construction of microarray chip for species determination or in phagemid version for pacient sera profiling to assess reactivity to a spectrum of various fish species meat.

Multivalent neoglycoconjugates with therapeutical potential

Department: Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology
Also available in programme: Biochemistry and Bioorganic Chemistry

Annotation

Galectins are animal lectins with affinity to ?-D-galactosides, which in vivo participate in, e.g., cancerogenesis, metastatic processes, immune response to tumorigenesis, and other cancer-related pathologies. The concentration of extracellular galectins in vivo significantly rises in connection with cancer and therefore they may be used as diagnostic markers in many cancer types, such as colorectal carcinoma. Targeted inhibition of extracellular galectins is one of the novel prospective therapeutic approaches to the treatment of pathologies associated with galectin overproduction. A range of recent structure-function studies revealed detailed structural requirements of individual galectins for high-affinity and selective ligands. The avidity of specific glycomimetics to target galectins may be greatly increased by the multivalent presentation. The aim of this work is to synthesize multivalent neoglycoconjugates carrying specific saccharidic ligands or glycomimetics with high selectivity and affinity to target galectins. The inhibition and binding potential of these neoglycoconjugates to galectins, in particular to galectin-1 and -3, will be assayed by in vitro methods of ELISA and surface plasmon resonance (SPR) with recombinant galectins and, later on, with selected cultures of cancer cells.

New deazapurine nucleosides and nucleotides as potential antivirals or cytostatics

Department: Department of Chemistry of Natural Compounds, Faculty of Food and Biochemical Technology
Also available in programme: Biochemistry and Bioorganic Chemistry
Theses supervisor: prof. Ing. Michal Hocek, DSc.

Annotation

We will design and synthesize new modified deazapurine nucleosides, nucleotides and prodrugs as inhibitors of polymerases or other enzymes of nucleotide metabolism, or as ligands (agonists or antagonists) of nucleotide receptors. Selected active compounds will be further optimized in order to identify preclinical candidates for development of potential antiviral or antitumour agents.

New heterocyclic inhibitors of selected protein kinases

Department: Department of Chemistry of Natural Compounds, Faculty of Food and Biochemical Technology
Also available in programme: Biochemistry and Bioorganic Chemistry
Theses supervisor: prof. Ing. Michal Hocek, DSc.

Annotation

We will design and synthesize modified heterocyclic compounds as inhibitors of selected protein kinases that are relevant targets for potential therapeutics of tumours or neurodegenerative diseases. A combination of rational design, synthesis of combinatorial libraries and optimization of hits will be used.

Novel approaches in the elimination of cancer cells and bacterial biofilms

Department: Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology

Novel glycomimetics as inhibitors of galectins

Department: Department of Chemistry of Natural Compounds, Faculty of Food and Biochemical Technology
Theses supervisor: Ing. Kamil Parkan, Ph.D.

Annotation

Carbohydrates are structurally diverse group of natural products which play an important role in numerous biological processes, including immune regulation, infection, and cancer metastasis. Unfortunately, native carbohydrates suffer from inherently weak binding affinities and poor pharmacokinetic properties. To enhance their potential as drug candidates, glycomimetics have been developed. They are more drug-like compounds, which mimic the structure and function of native carbohydrates. However, the advancement in carbohydrate research is relatively slow due to the problems associated with the complexity of carbohydrates structures and the lack of general synthetic methods. This problem could be solved using photoinduced chemistry under catalytic conditions. The use of photocatalysis is heading towards “greener” chemistry, where enhanced synthetic efficiency through the reduction of unnecessary waste is attained. The goal of the PhD project will be the development of synthetic methodologies for the preparation of various biologically prospective glycomimetics with affinity towards galectins (Gal-1, Gal-3, Gal-7), which are involved in many physiological functions, such as inflammation, immune responses, cell migration, autophagy, and signaling.

Preparation and biological activity of flavonoid metabolites

Department: Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology

Annotation

Flavonoids, as other food polyphenols, are subject to extensive metabolism in the intestine and liver. Biotransformation of flavonoids by the intestinal microflora leads in particular to the cleavage of ring C and the formation of simple phenolic compounds. The structure of the main intermediate of this cleavage is not yet fully experimentally confirmed. There are at least three options, chalcone structure, benzofuranone derivative and depside. All biotransformation products of the polyphenols by the intestinal microflora may also be subject to conjugation reactions such as sulfation, methylation or glucuronidation. The aim of this work is to prepare a series of potential intermediates and final metabolites of flavonoids in a quantity sufficient for their detailed characterization using spectral methods and their use as standards for metabolic studies by means of chemoenzymatic methods introduced in the Laboratory of Biotransformation. In addition, the end products will be evaluated for their biological potential by testing their antioxidant activity with in vitro assays. Thus, this interdisciplinary study will include methods of organic chemistry, chemistry of natural products, biochemistry, microbiology, molecular biology, experimental toxicology, and analytical chemistry.

Preparation and structural-functional analysis of virus-like and non-viral nanoparticles

Department: Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology
Theses supervisor: prof. Ing. Tomáš Ruml, CSc.

Annotation

The work is focused on the preparation of nanoparticles by self-assembly of viral structural proteins and on the basis of modified organic and inorganic structures. The particles will be surface modified to target pathogenic bacteria or tumor cells. Their ability to interact with target organisms for use in inhibiting, imaging and modulating cellular activity will be evaluated.

RNA metabolism related to the control of gene expression in the oocyte and embryo.

Department: Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology
Also available in programme: Biochemistry and Bioorganic Chemistry
Theses supervisor: Ing. Michal Kubelka, CSc.

Annotation

Fully grown oocyte utilizes only transcripts synthesized during earlier development. Mechanisms of mRNA metabolism in the mammalian oocyte are still far from being fully understood. In the first meiotic division, shortly after nuclear envelope breakdown, translational hotspots develop in the chromosomal area and in a region which previously surrounded the nucleus. This hotspot is controlled by the activity of the mTOR/4F axis. We suppose that the localization of specific mRNAs and their in situ translation is essential for the generation of developmentally competent oocyte. Thus, the objective of the current project is to investigate translation regulation and polysome profiling of the oocyte after NEBD. We will test our hypothesis that translation of specific mRNAs is essential for meiotic progression before first polar body extrusion. This represents a first attempt to unveil novel regulators of mTOR/4F axis and will add substantial information concerning translational control of specific transcripts after NEBD in order to understand molecular physiology of mammalian oocyte. The aims of project: High-throughput translation analysis after resumption of meiosis in the mammalian oocyte. Regulation of the mTOR/eIF4E pathway after nuclear envelope breakdown..Translation and genomic stability in the mammalian oocyte.Main methods: Next Generation Sequencing, biochemistry, molecular biology, FISH.

Retrovirus integration and epigenetic provirus silencing

Department: Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology
Theses supervisor: RNDr. Jiří Hejnar, CSc.

Annotation

Autonomous transcription of integrated retroviruses and retrotransposons is affected by genetic and epigenetic features of respective sites of integration. These, mostly suppressive effects silence proviral transcription activity by mechanisms such as DNA methylation and posttranslation modifications of adjacent histone molecules. Provirus silencing is a general feature of integrated retroviruses, but its extent and kinetics vary among different retrovirus species. We studied the role of integration site using single cell clones bearing the unique integrations of reporter vectors derived mostly from avian leukosis virus (ALV) or human immunodefficiency virus (HIV). This appproach enabled us to correlate expression of reporter gene and the epigenomic landscape at the site of integration. The topic to be open for one doctoral student will be the immediate early silencing of proviruses, which occurs quickly after integration or even during the integration event due to the extensive epigenomic shift and DNA repair processes. For this type of studies, it will be necessary to establish a special dual reporter system of vectors, which records the narrow and quickly vanishing pulses of transcriptional activity during and shortly after integration. Furthermore, integration preference or various retroviruses will be studied at the level of primary DNA sequence, epigenomic landscape, functional chromosomal segments and 3D genome structure. It is expected that this study will finish with alterations of chromatin contacts and topologically associated domains (TAD) of chromatin at the site of retrovirus integration.

Role of adhesion-GPCRs during viral infection of mammalian cells

Department: Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology
Also available in programme: Biochemistry and Bioorganic Chemistry
Theses supervisor: Mgr. Jan Weber, CSc.

Annotation

The proposed PhD project addresses the possible role of adhesion G protein-coupled receptors (aGPCRs) during viral infection of mammalian cells. The aGPCRs are intriguing class of seven-transmembrane proteins that play important role in neurodevelopment, immune defense and cancer, but their role during viral infection is mostly unexplored. Currently, we recognize 33 members of aGPCRs in humans but majority are orphan receptors with unknown function. We intend to search for specific aGPCR and/or cellular proteins in aGPCRs pathways involved in infections of mammalian cells and characterize their interaction with viral proteins. During postgradual study, student will learn how to work with cell cultures in biosafety level 3, perform proteomic and bioinformatic analyses and siRNA experiments for gene-knockdown in mammalian cells infected with various viruses. Proposed project will broaden our current knowledge about the role of aGPCRs in infections of mammalian cells and if successful, it can identify potential targets for antiviral therapy.

Structure and dynamics of glutamate receptors, theory and experiment.

Department: Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology
Theses supervisor: Ing. Jiří Černý, Ph.D.

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The proposed multidisciplinary project combines various experimental and theoretical strategies to refine structural elements of the glutamate receptor (iGluR) in functionally important states. We will extend the available structural data using a mammalian and insect cells expressed iGluRs. We will induce and characterize its functional state (activation kinetics, binding affinity, and single channel properties). Further, we will use the distance information from a structural mass spectrometry analysis as an input into all-atom adaptive enhanced sampling MD simulations to refine the original crystal structures and identify new structural motifs. We will gain highly accurate structural information on iGluR in its functionally important states and their role in iGluR structural transitions.

Structure and function of bacterial transcription system

Department: Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology
Theses supervisor: Ing. Jan Dohnálek, Ph.D.

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The bacterial transcription system is currently a focus of numerous research projects as an antibiotic target as well as posing a number of unanswered basic questions. We concentrate on analysis of structure and function of RNA polymerase from gram-positive bacteria, namely Mycobacterium smegmatis and Bacillus subtilis. We investigate the role of either recently discovered or not fully understood protein factors involved in the transcription machinery. Mycobacteria are medically important organisms containing serious pathogens. Bacillus subtilis is a representative organism of gram-positive bacteria, with some differences in transcription in comparison to mycobacteria. In this project selected RNA polymerase-associated proteins will be characterized in detail as for their structure and function, using techniques of molecular biology and integrative structural biology, including X-ray crystallography, small angle X-ray scattering and cryo-electron microscopy.

Study of natural biologically active substances transport through membrane systems

Department: Department of Chemistry of Natural Compounds, Faculty of Food and Biochemical Technology
Theses supervisor: doc. Ing. Martin Kuchař, Ph.D.

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This research work will deal with studies of biological membranes (skin, cornea, blood-brain barrier) in terms of their permeability to a number of natural biologically active substances with neuropsychopharmacological potential. Emphasis will be placed on the development and preparation of formulations containing CBD, THC derivatives and neuroactive steroids with suitable transport carriers across the skin, cornea and blood-brain barrier. The quantity of permeated substances and the changes in membranes caused by the passage of active substances and their carriers will be monitored. Commercial Franc diffusion cells will be used for the in vitro model of transdermal transport. The wok will also include the development of a new diffusion cell for transcorneal transport. The permeation of substances across the blood-brain barrier will be monitored by their pharmacological studies in the animal model with Wistar rats. An advanced separation technique coupled with mass spectroscopy will be used for the pharmacological study. Vibrational spectroscopy techniques will serve as advanced tools for the investigation of structural changes and the distribution of substances in membranes. The research will be carried out in cooperation with the International Eya Bank of Prague and the National Institute of Mental Health.

Study of the photocatalytic degradation of organic polutants from wastewater

Department: Department of Chemistry of Natural Compounds, Faculty of Food and Biochemical Technology
Theses supervisor: doc. Ing. Martin Kuchař, Ph.D.

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The work is focused on the utilization of liquid chromatography coupled to mass spectrometry to measure kinetics of photocatalytic degradation of selected biologically active pollutants in wastewater. Analytical methods elaborated in frame of the project will be further utilized for the identification of ultratrace quantities of degradation products. In silico prediction will be used to determine the degradation products and correlated with experimental data. The biological activity and possible toxicity of the products resulting from the photocatalytic degradation will be assessed in collaboration with the Institute of Experimental Medicine AV ČR.

Synthesis and application of ligands for P2X7 receptor imaging

Department: Department of Chemistry of Natural Compounds, Faculty of Food and Biochemical Technology
Theses supervisor: Ing. Michal Jurášek, Ph.D.

The development and application of organelle-targeted bioorthogonal cleavage reactions

Department: Department of Chemistry of Natural Compounds, Faculty of Food and Biochemical Technology
Also available in programme: Biochemistry and Bioorganic Chemistry
Theses supervisor: Ing. Milan Vrábel, Ph.D.

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Chemical reactions that can be performed under physiological conditions offer unique possibility to manipulate and study biological processes. Our group has a long-term interest in these, so-called, bioorthogonal reactions. They are mainly known as efficient chemical transformations leading to formation of covalent bonds. It has been only recently when the concept was extended to something what is known as bioorthogonal cleavage reactions. The power of this type of reactions is only slowly becoming recognized. In this project, we aim to develop and employ the release reactions, which will enable de-caging of small molecules within specific cellular compartments. We believe that such systems will offer not only a unique possibility to deliver and activate functional molecules within particular subcellular location, but in a broader sense, to shed light on the function of individual cellular organelles. This project combines organic chemistry with modern chemical biology experiments.

The mannose-6-phosphate/insulin-like growth factor 2 receptor as a target for memory enhancement and tumor suppression

Department: Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology
Also available in programme: Biochemistry and Bioorganic Chemistry
Theses supervisor: RNDr. Lenka Žáková, Ph.D.

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Identifying new compounds that effectively improve neurodegenerative disease is an urgent need. It has been recently shown that insulin-like growth factor 2 (IGF2) has an important role in enhancement of memory. IGF2 is a fetal growth factor that has also significant role in mature mammalian brain. The effect of IGF2 as a cognitive enhancer is rapid and persistent, and is mediated by mannose-6-phosphate/IGF2 receptor (M6P/IGF2R). M6P/IGF2R is a large transmembrane glycoprotein that except IGF2 can bind M6P-containing ligands and binding of one ligand may affect the binding another one. Moreover, overexpression of IGF2 plays important role in development of certain tumors and M6P/IGF2R can play a role as a tumor suppressor. This project is focused on (i) production of M6P/IGF2R or its constructs, (ii) preparation of IGF2R selective IGF2 analogues, and (iii) a libraries of small molecule compounds. This work should lead to important clinical applications of new IGF2 analogues.

The non-specific phospholipases C from Arabidopsis thaliana: structure-function relationship

Department: Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology

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This PhD work aims to elucidate the catalytic mechanism, structure and structure - function relationship of non-specific phospholipase C (NPC) from Arabidopsis thaliana. Six genes encoding NPCs (NPC1-NPC6) have been identified in the Arabidopsis thaliana genome. In our previous experiments with NPC4, it was found that this enzyme produces, besides the expected product - diacylglycerol, surprisingly also phosphatidic acid. This second activity seems to have been overlooked so far. In this project we will focus on the study of this phenomenon by mutagenesis and try to elucidate the structure and catalytic mechanism of these enzymes. The effect of mutations on plant phenotype will also be investigated.


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