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Biochemistry and Bioorganic Chemistry
Doctoral Programme,
Faculty of Food and Biochemical Technology
--- Careers--- Programme Details
Vypsané disertační práce pro rok 2025/26Biomimetic Approaches to the Total Synthesis of the Axinellamines
AnnotationThe axinellamines belong to the most complex alkaloids with interesting biological properties. With this project biomimetic approaches will be explored to enable short total syntheses of the natural products themselves and of analogs. Their biological profile will be investigated in collaboration.
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Study place:
Institute of Organic Chemistry and Biochemistry of the CAS
Defined chitosan conjugates for biomedical applications
AnnotationChitin is the second most abundant polymer in nature. Partial deacetylation of chitin produces chitosan, a linear polymer composed mainly of glucosamine units (GlcN) and to a lesser extent of N-acetylglucosamine units (GlcNAc) linked ?(1?4) by glycosidic bonds. Chitosan is biocompatible and can therefore be advantageously used in a variety of biological and biomedical applications. For many biological applications, it is advantageous to work with shorter chains of chitosan, the so-called chitooligosaccharides (COS). COS have been intensively researched for decades in the fields of medicine, pharmaceuticals, textile industry, food industry and agriculture. Despite their tremendous potential use, poorly characterized heterogeneous mixtures are used in most studies due to the unavailability of well-defined COS. The thesis will focus on the preparation of authentic, pure and fully structurally characterized COS and chitosans and their analysis. Subsequently, the defined COS chains will be used as carriers for multivalent presentation of bioactive carbohydrates, and their bioactivities will be studied, especially in biological tests with lectins.
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Study place:
Institute of Microbiology of the CAS
Flavonoid-derived metabolites as standards for metabolic studies
AnnotationFlavonoids are plant food components that are known to be intensively metabolized in the gut and to interact with and influence the composition of the gut microbiome. Flavonoids are also subject to rapid biotransformation in the II phase, whereby mainly corresponding sulfates and glucuronides are formed. The biotransformation of polyphenols by the gut microbiota also leads to cleavage of the C-ring and the formation of simple phenolic substances. The aim of this PhD project is the optimization of chemoenzymatic methods for the synthesis of a library of natural flavonoids (myricetin, luteolin, kaempferol, naringenin, hydroxyphenylacetic acid and hydroxyphenylpropionic acid) and their metabolites (sulfates, glucuronides and depsides). Natural and mutant enzymes from bacterial and fungal sources (arylsulfotransferases, glucuronidases, quercetinase) are used for this purpose. These enzymes are expressed in microbial expression systems (E. coli, P. pastoris), characterized and optimized for the synthesis of the desired metabolites. The compounds are then used as standards for metabolic studies carried out in collaboration with our partner laboratories.
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Study place:
Institute of Microbiology of the CAS
Derivatives of natural mitotic poisons for medical applications
AnnotationThe natural products Taxol and vinblastine are established drugs in the treatment of various malignant pathologies. Colchicine is an alkaloid used in the treatment of severe inflammation. Although colchicine has potent antitumor properties, no derivative has yet reached the market. The potential of colchicine for targeting γ-tubulin is also significant. The group has original and unpublished knowledge on this effect. The main problem with Taxol is the increasing resistance of tumors to this treatment. The aim of the work will be (1) to synthesize new colchicine derivatives designed as γ-tubulin inhibitors, (2) to design and synthesize new potent Taxol derivatives with reduced P-gp induction, and (3) to design and synthesize new precursors of Taxol and vinblastine designed for binding to a polymer targeting tumor tissue.
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Study place:
Department of Chemistry of Natural Compounds, FFBT, VŠCHT Praha
Design and synthesis of novel methyltransferase Inhibitors
AnnotationThe Ph.D. student will design and synthesise novel methyltransferase (MTase) inhibitors targeting viral, fungal or human MTases. The student will use in silico approach to speed up the development of potential drugs, but the main part of the assignment will be the organic synthesis. Preparation of suitable ligands bearing a fluorescent tag will enable the efficient development of a screening assay.
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Study place:
Institute of Organic Chemistry and Biochemistry of the CAS
Display of proteins on DNA
AnnotationNucleotides bearing specific ligands or reactive groups will be designed and synthesized, from which modified DNA will be synthesized by enzyme methods and used to attach target proteins. Applications will include multi-enzyme systems.
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Study place:
Institute of Organic Chemistry and Biochemistry of the CAS
Enzymatic synthesis of biologically active chitooligomers
AnnotationChitooligomers are ?-1-4-linked oligosaccharides composed of N-acetylglucosamine and glucosamine units and their biological activity depends mainly on their degree of polymerization, degree of acetylation, and acetylation pattern. Chitooligomers are known for their ability to induce an immune response in plants and could thus be used as natural crop protection agents against microbial pests. This PhD project will focus on the efficient enzymatic preparation of chitooligomers with different degrees of polymerization and acetylation, in particular chitooligomers with degrees of polymerization 6-10 and different degrees of acetylation are in demand and not yet available. Microbial natural and mutant glycosidases, particularly chitinases and ?-N-acetylhexosaminidases, and chitin deacetylases from bacterial and fungal sources will be used for this purpose. These enzymes will be expressed in microbial expression systems (E. coli, P. pastoris), characterized, and optimized for the synthesis of the desired chitooligomers. The biological activities of the prepared chitooligomers, especially concerning plant pest protection, will be tested in collaboration with Czech and foreign partners of the laboratory.
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Study place:
Institute of Microbiology of the CAS
Enzymatic synthesis of modified oligonucleotides and DNA bearing several modifications at specific positions
AnnotationModified 2'-deoxyribonucleoside-triphosphates will be synthesized and used in enzymatic synthesis of oligodeoxyribonucleotides and DNA bearing several modifications at specific positions using a novel approach involving repeated annealing of RNA templates, primer extension and RNA digestion. Applications will include the spatially defined attachment of several different biomolecules, particularly proteins, to DNA.
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Study place:
Institute of Organic Chemistry and Biochemistry of the CAS
Evolutionary origin of terpenoid biosynthesis in insects
AnnotationTerpenoid secondary metabolites are used by organisms for communication and defense, and their biological activities are exploited by industries such as pharmaceuticals, cosmetics, or food and flavour. This PhD project addresses the question of evolutionary origin of terpenoid biosynthesis in insects. Terpene synthases (TPS) are key enzymes responsible for the conversion of prenyl pyrophosphates into terpenes, and insect TPSs are unrelated to their plant or microbial counterparts. They have evolved multiple times independently in different insect lineages. Our understanding remains limited in terms of their reaction mechanisms and structure-activity relationships. Within this PhD project, the doctoral candidate will functionally characterize a set of insect terpene synthases from unrelated insect clades and define their common and idiosyncratic structural features acquired during their multiple independent origins. This PhD project is funded by the European MSCA Doctoral Network ‘ModBioTerp’ and the grant support for the broader research project is funded by Ministry of Education, Youth, and Sports (2024-2027).
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Study place:
Institute of Organic Chemistry and Biochemistry of the CAS
Glycine alkoxyamines for New Bioconjugation Methodologies
AnnotationWe just accomplished approaches to glycine alkoxyamines, which hold large promise in bioconjugation. With this project the potential of these non-natural amino acid derivatives for approaching new peptide architectures will be explored.
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Study place:
Institute of Organic Chemistry and Biochemistry of the CAS
Immunochemical detection of drugs and illegal substances used in doping
AnnotationThe abuse of drugs and illegal substances in everyday life, as well as in sports, is currently a major societal issue. A number of instrumental methods have been developed for the detection of these substances, but they require sophisticated instrumentation and experienced analysts. The aim of this thesis is to develop methods that are technologically and economically cost-effective, and, in addition, as user-friendly as possible. The work will focus on the use of immunochemical principles, specifically enzyme-linked immunosorbent assays (ELISA) and immunochromatographic tests, both of which allow for the effective detection of low concentrations of target analytes even in complex matrices. The thesis will also address the optimization of these methods for specific types of illegal substances and the exploration of new approaches to improve their reliability and sensitivity.
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Study place:
Department of Biochemistry and Microbiology, FFBT, VŠCHT Praha
Inhibitors of methyltransferases – design and synthesis of potential new drugs
AnnotationThe PhD student will focus on the design and organic synthesis of new methyltransferase inhibitors, whether derived from viral, fungal, or human sources. In the course of developing these compounds, the candidate will employ in silico molecular modeling to streamline and accelerate the search and optimization of inhibitors. Nonetheless, the main emphasis of the project will remain on the organic synthesis of potential therapeutic agents. Additionally, the project will include the preparation of ligand analogs equipped with suitable tags, whether fluorescent or functional (e.g., biotin for pull-down assays, thalidomide for PROTAC technology).
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Study place:
Institute of Organic Chemistry and Biochemistry of the CAS
Integrated Stress Response in survival or cell death.
AnnotationEukaryotické buňky si vyvinuly několik mechanismů, jak se vyrovnat s různými stresory prostředí. Patří mezi ně komplexní signální dráha označovaná jako integrovaná stresová odpověď (ISR), která vede buňky buď k adaptaci nebo ke smrti. Zatímco jejími vnějšími spouštěči jsou kyslík, nedostatek živin nebo virové infekce, hlavním vnitřním stresorem je hromadění nesložených proteinů v lumen endoplazmatického retikula (ER). ISR může být také indukována aktivací onkogenů. Reakce je „integrovaná“, protože všechny stresové signály jsou přenášeny rodinou čtyř serinových/treoninových kináz a konvergují do jediné události, kterou je fosforylace ? podjednotky eukaryotického iniciačního faktoru translace 2 (eIF2?). Provedli jsme komplexní screening, abychom zjistili, jaké mRNA a lncRNA jsou překládány za normálních podmínek versus akutní nebo chronické (pro-apoptotické) ISR. Cílem navrhovaného projektu je vybrat klíčové mRNA z našeho robustního screenu a prozkoumat jednak molekulární mechanismus jejich specializované translace, jakož i úlohu jejich proteinových produktů za daných stresových podmínek.
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Study place:
Institute of Microbiology of the CAS
Liquid chromatography-mass spectrometry for comprehensive characterization of the metabolome and lipidome of biological samples
AnnotationOver the last decade, mass spectrometry-based metabolomics and lipidomics have become key platforms for the comprehensive profiling of polar metabolites and complex lipids in biological samples such as plasma, serum, urine, and tissues. Liquid chromatography coupled with mass spectrometry (LC-MS) is the preferred technique in metabolomics and lipidomics, enabling effective separation and detection of metabolites and lipids. However, there remains a lack of comprehensive data on the metabolome and lipidome of biofluids and tissues that is easily accessible and reusable for future studies. This Ph.D. project aims to develop novel approaches for the comprehensive characterization of the metabolome and lipidome in biological samples. Specifically, it will focus on (i) integrating targeted and untargeted methods, (ii) expanding the coverage of spectral libraries for metabolite annotation, and (iii) employing bioinformatics tools for visualization and interpretation of metabolomics and lipidomics data. The work will be conducted at the Institute of Physiology CAS and financially supported by grants from GACR, MSMT, and AZV.
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Study place:
Institute of Physiology of the CAS
Cryo-EM structural biology of diseases: Rationally designed viral-RNA based inhibitors of influenza RNA polymerase
AnnotationEffective treatment against influenza viruses (Flu) suffers from virus resistance. Therefore, there is a great demand for exploring new drug targets and developing effective novel antivirals. This is challenging, since there is only a limited number of antiviral targets for rational drug design. This project will tackle both; it will explore and verify a new target and develop inhibitors against it. Cutting edge results in structural biology of the influenza RNA-dependent RNA polymerase (FluPol), identified a common general mechanism of Flu RNA transcription and replication cycle. The mechanism is entirely dependent on binding of viral endogenous RNA molecules to specific sites on the FluPol. Aided by already existing cryo-EM structures of FluPol, we will design inhibitors based on the sequence, atomic structure and interactions with the protein, and add extensive chemical modification to these viral RNAs. We will then test whether they can inhibit FluPol by in vitro and in cell-based experiments. Targeting these RNA binding sites and using RNA-scaffold based molecules is an innovative concept and expected to be robust in respect to the development of viral resistance. Altogether, the approach has great potential to bring a new universal paradigm to the field of antiviral drug discovery.
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Study place:
Institute of Organic Chemistry and Biochemistry of the CAS
Metabolic engineering for bioproduction of terpenoids
AnnotationOur lab combines cutting-edge experimental (e.g., LC-MS, metabolomics, RNA-seq) and computational (e.g., bioinformatics, molecular networking, machine learning) approaches to develop new workflows for the discovery and utilization of bioactive molecules derived from plants. The aim of this project will be to engineer new microbial platforms for the bioproduction of terpenoid precursors and terpenoids derived from them.
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Study place:
Institute of Organic Chemistry and Biochemistry of the CAS
Muscle non-shivering thermogenesis for obesity treatment
AnnotationOur recent results obtained in mice suggested a possibility to reduce obesity through adaptive enhancement of non-shivering thermogenesis (NST) in skeletal muscle. This PhD project focuses on the characterization of the: (i) role of genetic background of mice on muscle NST and its subsequent effect on obesity; (ii) mechanisms responsible for the permanent setting of muscle NST levels during a critical time window shortly after birth, as indicated by our unpublished results; and (iii) in vitro effects of candidate compounds on energy expenditure in muscle satellite cells derived from mice differing in capacity for muscle NST. The project will employ: (i) long-term experiments in mice with in vivo phenotyping of whole-body metabolism; (ii) utilization of omics techniques and associated data analyses; and (iii) application of bioanalytical methods in vitro. This research will deepen understanding of muscle NST and its potential as a novel therapeutic target for obesity treatment. By exploring the genetic and developmental factors influencing NST, as well as testing effects of selected compounds in muscle cells, this project may pave the way for innovative obesity interventions. Project will be conducted at the Institute of Physiology of CAS, with the total agreed income guaranteed during the 4-year project.
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Study place:
Institute of Physiology of the CAS
Discovery of unique chemical structures of plant metabolites
AnnotationOur lab combines cutting-edge experimental (e.g., LC-MS, metabolomics, RNA-seq) and computational (e.g., bioinformatics, molecular networking, machine learning) approaches to develop new workflows for the discovery and utilization of bioactive molecules derived from plants. This project will focus on screening many plant species using liquid chromatography mass spectrometry to discover and isolate unique chemicals (metabolites), including basic characterization of their bioactive potential.
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Study place:
Institute of Organic Chemistry and Biochemistry of the CAS
Dissecting molecular basis of nonhost resistance to <i>Leptoshaeria maculans</i>in plants of the Brassicaceae family
AnnotationOilseed rape (Brassica napus) is the second most important oilseed crop in the world. Its production is limited by pathogens and pests. Among the most serious of these is the ascomycete Leptosphaeria maculans, the causal agent of phoma stem canker. The project focuses on non-host resistance to this pathogen, which is based on basic mechanisms of plant immunity and is not easily overcome by virulent races of the pathogen selected from the population. Using the natural variability of the model plant Arabidopsis thaliana and approaches of molecular biology, microbiology, bioinformatics, advanced microscopy and plant physiology, the work will aim to unravel the nature of nonhost resistance in B. napus and other plants of the Brassicaceae family.
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Study place:
Department of Biochemistry and Microbiology, FFBT, VŠCHT Praha
Advanced glycomimetics in neurodegeneration research
AnnotationAlzheimer's disease (AD) represents a significant health and socioeconomic challenge. This project aims to develop innovative multi-targeted therapeutic approaches through the creation of dual/hybrid compounds. These compounds will combine optimized inhibitors of O-N-acetyl-?-D-glucosaminidase (OGA) and acetylcholinesterase (AChE) inhibitors using covalent conjugation via an optimized linker. Targeting both key biological receptors involved in AD progression offers the potential for more effective therapy. The study will include an evaluation of carbacyclic glycomimetics developed within the Czech-Austrian-Croatian collaboration, including testing their permeability across the blood-brain barrier (BBB) using static and dynamic models, increasing O-GlcNAcylation, and reducing Tau protein hyperphosphorylation. Advanced models of human AD, such as brain organoids, and in vivo efficacy testing in tauopathic mouse models will also be part of the research in collaboration with the Institute of Experimental Medicine of the Czech Academy of Sciences. The project combines cutting-edge research with practical applications and provides a unique opportunity to engage in a multidisciplinary team.
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Study place:
Institute of Microbiology of the CAS
Protonation and coordination states in protein – nucleic acids interactions
AnnotationThe project is focused on experimental description of protonation of chemical groups, which is critical for protein-nucleic acid interactions. A model system of metal-dependent nucleases will be subjected to experimental methods of structure analysis – atomic resolution X-ray crystallography and neutron crystallography in connection with special computational approaches. The results will include characterisation of protonation of the individual chemical groups in their interactions in dependance on the nucleic acid type and also on the coordination of the metal cluster of the model active site of S1-P1 nucleases. The candidate is expected to have at least basic knowledge and skills in the methods of structure analysis of biological molecules and of biochemistry.
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Study place:
Institute of Biotechnology of the CAS
The benefit of methods detecting specific antibodies against platelets and granulocytes in transfusion medicine and clinical practice
AnnotationAntiplatelets and antigranulocytes antibodies cause various clinical conditions in patients: autoimmune, alloimmune cytopenias (thrombocytopenia, granulocytopenia), but can also be a causative complication of transfusion therapy and transplantation. Specific antiplatelet and antigranulocyte antibodies are underdetected. Using methods detecting specific antiplatelet and antigranulocyte antibodies will increase the incidence of platelet and granulocyte antibodies. Laboratory diagnosis of clinical conditions caused by antibodies to platelets and/or granulocytes and transfusion safety will also improve. The doctoral thesis will focus on methods for detecting specific antibodies against platelets and/or granulocytes and their benefit to the diagnosis of conditions caused by these antibodies.
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Study place:
Department of Biochemistry and Microbiology, FFBT, VŠCHT Praha
Redox mechanisms of insulin secretion
AnnotationThe central role of pancreatic beta cell, insulin secretion, is still not fully understood, concerning molecular mechanisms. We have revealed that redox (H2O2) signal is essential for glucose-stimulated insulin secretion (GSIS, the source is NADPH oxidase 4, NOX4) and fatty acid-stimulated insulin secretion (FASIS, the source are mitochondria). The concomitant metabolic pathways are not yet completely characterized for all insulin secretagogoues, e.g. for branched-chain amino acids and others. Therefore, we will develop mitochondria-specific metabolomics and proteomics after rapid magnetic separation of mitochondria having HLA antigen expressed on the surface of their outer membrane. Islets will be isolated from the respective transgenic mice. Using 13C-metabolites, we will study the respective metabolic pathways as well as redox homeostasis in physiological and simulated diabetic (pathological) conditions. We will also judge conditions for lipotoxicity and role of lipid metabolism. See Ref. doi: 10.1016/j.redox.2024.103283 and doi: 10.2337/db19-1130.
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Study place:
Institute of Physiology of the CAS
Regulation of growth and metabolism by the mTOR pathway
AnnotationMy lab has a long-standing interest in the regulation of growth and metabolism. This interest stems from our early work on the pathway anchored by mTOR protein kinase, which we now appreciate is a major regulator of growth and anabolism responds to nutrients. Because we found that lysosomes play a key role in the activation of mTORC1 by nutrients, we began to study lysosomes as well as other organelles, like mitochondria. We developed methods for the rapid isolation and profiling of these organelles (e.g., Lyso-IP), and used them to deorphan the functions of disease-associated genes. Because mTORC1 senses nutrients, we also became interested in the metabolic pathways that cells to use incorporate biomass and generate energy. (1) Nutrient sensing by mTORC1 in vitro and in vivo. We seek to identify the glucose sensor for the mTORC1 pathway; discover nutrient sensors in animals beyond mammals; understand how the nutrient sensors function in vivo. (2) Lysosomes in normal physiology and disease.We seek to understand how common and rare neurodegenerative diseases impact lysosomal function and identify the contents of lysosomes in specialized cells. (3) In collaboration with chemists, we will develop drug-like molecules that target mTOR pathway components as well lysosomal proteins.
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Study place:
Institute of Organic Chemistry and Biochemistry of the CAS
Studies of mitochondrial lipotoxic dysfunction in pancreatic cancer
AnnotationInhibition of mitochondrial metabolism in non-adipose tissues results in triglyceride (TG) synthesis and accumulation in lipid droplets (LDs). This is caused by the inhibited import of activated fatty acids (FAs) into mitochondria, which leads to the redirection of FAs into LDs and protects from the deleterious effects of FA oxidation (Gotvaldová et al 2024, PMID: 38532464). We aim to investigate the mechanisms that govern the utilization of FAs in mitochondria as opposed to TG synthesis and how this is reflected in mitochondrial lipotoxicity. We will use cell knockout of DGAT1, which is partially defective in TG synthesis, and also knockout of the mitochondrial enzyme CRAT, which is able to induce pancreatic tumorigenesis via epigenetic regulations. In this project, we aim to identify a lipotoxic culprit responsible for mitochondrial damage that affects mitochondrial function and cell survival. Using multi-omics approaches, we will identify metabolic and gene signatures associated with mitochondrial oxidative and lipotoxic damage. We will also focus on post-translational modifications in knockout models. The goal of the project is to identify crosstalk mechanisms between cellular compartments, namely mitochondria, peroxisomes and LDs, focusing on FA dynamics within. Our work should link the metabolic effects of mitochondrial oxidative processes to anabolic metabolism and reveal additional mechanisms of metabolic signaling in cancer cells.
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Study place:
Institute of Physiology of the CAS
Light upconversion paramagnetic nanoparticles for monitoring beta cell mass in pankreas and in vivo by magnetic resonance
AnnotationAccurate methods to detect pancreatic ?-cell mass and functionality in vivo are essential to better understand the pathogenesis of diabetes associated with pancreatic ?-cell deficiency and to develop new treatment options. Therefore, we will develop polymer-coated paramagnetic core-shell upconversion nanoparticles (UCNPs) conjugated with small GLP-1 receptor ligands (GLP-1 peptide, liraglutide or agonist 3) to target and monitor pancreatic ?-cell mass using magnetic resonance imaging (MRI) and luminescence. The newly developed UCNPs will be optimized in size to penetrate blood capillaries of the native and transplanted pancreatic islets and modified for long-term monitoring. Ultrasmall UCNPs (5 nm) will serve as a contrast agent for electron microscopy to visualize and count mtDNA nucleoids in ?-cells, which are typically reduced in diabetes. The specificity, safety and efficacy of all developed UCNPs will be validated in in vitro and in vivo models using multimodal imaging including luminescence, MRI and electron microscopy. See Ref. doi: 10.1021/acsami.2c04274.
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Study place:
Institute of Physiology of the CAS
Synthesis and characterization of glycomimetics for targeted therapeutic applications
AnnotationCarbohydrates are essential biomolecules that play a crucial role in various biological processes, such as cell signaling, adhesion, recognition, and intercellular communication. In the context of biomedicine, carbohydrates and their derivatives represent important targets for the development of new therapeutic agents. Glycomimetics are synthetic analogs of carbohydrates that mimic their biological functions; however, unlike natural carbohydrates, they are stable against chemical and enzymatic hydrolysis, enhancing their therapeutic potential and applicability. The aim of this doctoral project is to design, synthesize, and characterize new glycomimetic structures with potential applications in targeted therapy and diagnostics. The focus will be on developing compounds with high specificity and affinity for receptors involved in pathological processes, such as inflammation, infections, and tumor growth. The final glycomimetics will undergo biological testing to evaluate their therapeutic and diagnostic potential. This topic is primarily intended for graduates of chemistry or pharmaceutical fields. Throughout the project, the student will acquire in-depth knowledge of organic synthesis, separation and purification techniques, and modern structural analysis methods (NMR, MS, HPLC). The project will also include basic biological evaluation of the synthesized compounds.
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Study place:
Department of Chemistry of Natural Compounds, FFBT, VŠCHT Praha
Syntesis of new psychoplastogenic compounds as potential neurochemical tools for investigating human cognition
AnnotationObjectives 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, phenethylamine classes and other natural alkaloids, 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.
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Study place:
Department of Chemistry of Natural Compounds, FFBT, VŠCHT Praha
Total Syntheses of Complex Indoloterpene Alkaloids and Their Analogs
AnnotationWith the project, synthetic approaches to complex indoloterpene and their analogs displaying wide-ranging biological activity will be developed.
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Study place:
Institute of Organic Chemistry and Biochemistry of the CAS
The role of platelets in congenital and acquired disorders of hemostasis
AnnotationPlatelets are one of the most important parts of hemostasis. Thrombocytopathy, or disorders of platelet function, is a group of difficult-to-diagnose rare congenital diseases due to complex and often inaccessible diagnoses. Thrombocytopathy research currently aims to find mutations causing bleeding manifestations in patients who cannot be included in any of the historically defined categories of congenital platelets disorders. However, for proper diagnosis and treatment, in addition to the genetic basis, it is necessary to characterize functional disorders causing bleeding phenotype. In this project, we will deal with expanding the test scheme to cover these unfulfilled diagnostic requirements. Platelets, and especially receptors on platelets, participate in venous thrombosis, arterial thromboses, and prothrombotic inflammatory events. Another part of the project will be the characterization of receptors and possibly other molecules (e.g. High Mobility Group Box 1-HMGB1) and their role in platelets activation in these serious civilization diseases.
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Study place:
Department of Biochemistry and Microbiology, FFBT, VŠCHT Praha
Creating a suitable microenvironment for vascularization of tissue-engineered constructs
AnnotationVascularization of tissue substitutes and models is a key issue in tissue engineering. In the case of tissue substitutes, it ensures their long-term viability after implantation in the recipient, and in the case of tissue models (which are intended to replace or at least significantly reduce the use of laboratory animals in modern 21st century science), it ensures their adequate morphology and function. Unfortunately, even in modern tissue engineering, the vascularization of tissue constructs is not yet satisfactorily solved. It is known that in three-dimensional (3D) cell culture systems, especially in hydrogel-based systems, endothelial and mesenchymal stem cells (MSCs) spontaneously form hollow tubular capillary-like structures by "self-assembly" (doi: 10.33549/physiolres.935294; doi: 10.1016/j.biotechadv.2018.03.011). Therefore, in this work we will optimize hydrogels made of natural polymers (e.g. collagen, fibrin) and especially synthetic polymers (e.g. PEO or Pluronic, functionalized with adhesion oligopeptides such as RGD) for the formation of pre-capillaries from vascular endothelial cells and MSCs from adipose tissue, bone marrow or Wharton's jelly of the umbilical cord. However, the differentiation of stem cells into cells of the desired tissue (e.g. adipocytes, osteoblasts or vascular smooth muscle cells) often impairs the formation of pre-capillaries (doi: 10.1089/ten.tea.2020.0330). Therefore, we will look for the correct timing of this differentiation (e.g., already before pre-capillary formation), the appropriate composition of the culture medium (i.e., the appropriate ratio of vasculogenic and differentiation medium), and the appropriate ratio of stem and endothelial cells. Last but not least, we will ensure appropriate mechanical properties of the construct, e.g. by reinforcing it with nanoparticles that also release growth and differentiation factors (doi: 10.3390/ijms24065692).
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Study place:
Institute of Physiology of the CAS
Utilization of liquid chromatography-mass spectrometry for the pharmacokinetic study of psychoactive substances
AnnotationThe new psychoactive substances form a structurally diverse group with a wide range of effects on the central and autonomic nervous system. A number of substances have potential in the treatment of mental disorders, neurodegenerative diseases or pain therapy. The work will be focused on analysis of important biologically active substances in complex biological matrixes. These results will be an important part of ongoing neuropsychopharmacological research and preclinical trials of psychoactive substances in BAFA Laboratory. The most highlighted part will be the optimization of the biological samples preparation and development of the suitable LC method coupled with mass spectrometry.
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Study place:
Department of Chemistry of Natural Compounds, FFBT, VŠCHT Praha
Development and validation of a methodology for the determination of fatty acids on the GC-MS platform and its practical application
AnnotationGlucocorticoids increase gluconeogenesis, decrease glucose utilization, and promote lipolysis, which contributes to insulin resistance. Progesterone also increases insulin resistance and lipolysis, which increases free fatty acid levels, while its metabolite allopregnanolone affects lipid metabolism indirectly through stress hormones. Adrenal androgens can improve insulin sensitivity due to anti-inflammatory effects, but elevated levels can worsen insulin resistance. Estrogens also improve insulin sensitivity and lipid metabolism, while their decrease increases the risk of diabetes. The aim of the dissertation is to develop and validate a methodology for simultaneous determination of the fatty acid spectrum using a GC-MS platform. This methodology will subsequently be applied to investigate the connections between changes in the steroidome, fatty acid profile, and insulin tolerance disorders in patients with a history of gestational diabetes. The research results will contribute to a deeper understanding of the pathophysiology of insulin resistance and provide a basis for the diagnostic use of the developed methodology.
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Study place:
Department of Chemistry of Natural Compounds, FFBT, VŠCHT Praha
Development of immunochemical methods for the detection of HHC and kratom
AnnotationKratom and new phytocannabinoids such as HHC have become a significant phenomenon in recent years, with products containing these substances being freely available and having a wide user base. This project focuses on the development of certified field tests for the preliminary screening of acute salivary intoxication. The field tests will be based on the principle of competitive immunochromatographic methods using commercial and newly prepared monoclonal or polyclonal antibodies. The aim is primarily to provide the traffic police with a tool to control drivers affected by these substances.
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Study place:
Department of Biochemistry and Microbiology, FFBT, VŠCHT Praha
Deciphering Lipid Metabolism in Cancer: Integrative Approaches in Metabolomics, Fluxomics, and Metabolic Engineering
AnnotationThis PhD project investigates the rewiring of lipid metabolic pathways in cancer using an integrative approach combining metabolomics, fluxomics, metabolic engineering, and in silico modeling. The research aims to deconvolute complex lipid metabolic pathways through metabolic flux analysis and stable isotope tracer studies, supported by Python-based data processing pipelines and advanced computational modeling. The study incorporates experimental work, including cancer cell culture systems and in vivo mouse models, to validate findings and quantify metabolic fluxes under physiological and pathological conditions. In silico simulations of lipid metabolism will be used to predict pathway behavior and identify potential intervention points. Machine learning approaches will aid in biomarker discovery and the prediction of metabolic vulnerabilities, offering insights into the mechanisms driving cancer progression and potential therapeutic targets. This interdisciplinary project bridges computational biology, biochemistry, and experimental cancer research, contributing to our understanding of lipid metabolism and the development of precision strategies for metabolic engineering and cancer therapy. The work will be conducted at the IPHYS CAS, where the metabolomics and proteomics service laboratory is located. The work is financially secured in terms of material and full time position.
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Study place:
Institute of Physiology of the CAS
3D superresolution microscopy for accessing mitochondrial ultramorphology
Annotation3D 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. See Ref. doi: 10.1089/ars.2022.0173.
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Study place:
Institute of Physiology of the CAS
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Updated: 20.1.2022 16:26, Author: Jan Kříž