OBJECTIVES: The research aims the field of nanomedicine, especially to immunopharmacotherapy of cancer, infection diseases (vaccines) and diagnostics. Outcomes (publications and eventually patent applications) will contribute to development of modern immunotherapeutics like vaccines and adjuvants, targeted anticancer/antiviral drugs and theranostics for in vivo imaging and monitoring the progress of treatment.

FOCUS: Doctoral research projects focus on preparation and complex characterisation of biocompatible functionalised nanoparticles applicable for development of modern therapeutics and theranostics. Student will benefit from world class infrastructure at VRI, including laboratory of physical-chemical methods (microfluidic system, MALS, MADLS, NTA, TRPS, UV VIS/CD/FL/FT-IR spectroscopy, Field Flow Fractionation, thermal methods like DSC and ITC, laboratory of microscopic methods (AFM, TEM, SEM and confocal microscopy), laboratory of tissue culture and biotechnology (FPLC/HPLC, various unique bioreactors for production of recombinant proteins, ultracentrifugation, QRT-PCR, multifunctional multiplate reader, flow cytometry and cell sorter), laboratory of surgery and in vivo imaging (microcomputer tomography microCT and optical whole body scanner) and animal house for experiments on small and large animals, laboratory of histology.

EXAMPLES of potential doctoral projects:

• Preparation and formulation of mRNA in liposomes and evaluation of transfection potential in vitro and in vivo, study of immune response in vivo on mice model
• Expression, purification and characterisation of recombinant proteins/antigens (e.g. HIV-1, influenza, Borrelia), construction of experimental vaccines and study of immune response in vivo
• Preparation of nanoparticle based contrast agents (e.g. gold nanoparticles) for in vivo imaging via microCT and MRI: tumour and thrombi as targets
• New antiviral drugs and their formulation, modification for targeting of macrophages, testing in tissue culture and in vivo models
• New molecular adjuvants and immunomodulators: formulation in nanoliposomes, testing in models in vitro and in vivo
• Nano and microstructures for non-invasive vaccination: preparation, characterisation and testing in in vivo models with model antigens, evaluation of immune response (mice, pig)
• Physiologically active compounds from venom, characterisation, purification, preparation of antisera

MORE INFORMATION: www.vri.cz/en//

PLEASE NOTE: before initiating the formal application process to doctoral studies, all interested candidates are required to contact Ass. Prof. RNDr. Jaroslav Turánek, Res. Prof. (turanek@vri.cz) for informal interview.

Školitel

prof. RNDr. Jaroslav Turánek, DSc.

BACKGROUND: Cardiovascular diseases currently contribute the biggest burden of the mortality worldwide. The molecular mechanisms behind are frequently underexplored.
Current pre-clinical research of cardiovascular diseases utilizes animal models predominantly. However, they provide low throughput and may fail to recapitulate certain aspects of human pathophysiology. That is why an in vitro model can be a suitable alternative especially if combined with biological material of human origin. OBJECTIVES: Provide insights into selected aspects of a cardiovascular disease using a specifically tailored vasculature model.
FOCUS: The group of Jan Víteček is focused on thrombolysis in connection with ischemic stroke treatment and the role of blood flow in vascular pathophysiology.
EXAMPLES of potential student doctoral projects:
Mechanisms of thrombolysis and recanalization; Biochemical mechanisms of clot thrombolytic resistance; Role of blood flow in development of aneurysms and stenoses; Electrical phenomena in vasculature homeostasis.
METHODS: Vascular model construction, cell cultures, mechanobiological characterisation of blood clots, fluorescence confocal and electron microscopy, basic approaches of biochemistry and molecular biology.
MORE INFORMATION:
https://www.ibp.cz/en/research/departments/biophysics-of-immune-systems/research-profile/group-of-vitecek-jan
https://www.strokebrno.com/members/institute-of-biophysics/
PLEASE NOTE: Before initiating the formal application process to doctoral studies, the candidate is required to contact Jan Víteček for an informal discussion.

Školitel

Mgr. Jan Víteček, Ph.D.

BACKGROUND: Extremely acidophilic and chemolithotrophic microorganisms are well known for their ability to dissolve metals directly via redoxolysis or indirectly via acidolysis and complexolysis. The microbial oxidation of ferrous iron and elemental sulfur generates ferric iron and sulfuric acid, facilitating the dissolution of oxide or sulfide minerals and releasing the incorporated metals. FOCUS: Our research group aims to study the metabolism of extreme acidophiles and their role in recovering valuable metals from natural and waste minerals. EXAMPLES of potential student doctoral projects: Study of metabolic pathways related to the production of important metabolites in extreme acidophiles using a multi-omics approach; characterize proteins essential for their metabolism and adapt to extreme environments using heterologous protein expression. METHODS: Microbial cultivation up to the level of bioreactors; biochemical methods: isolation, separation, purification, and identification of biomolecules (ultrafiltration, ultracentrifugation, gel electrophoresis, FPLC, HPLC); enzyme kinetics (UV/VIS spectrophotometry, ITC, MST); molecular biology and genetic engineering methods: PCR, qPCR, RT-qPCR, immunodetection, sequencing, cloning, transformation, mutagenesis, protein-protein interactions (SPR); omics methods: genomics and transcriptomics (NGS), proteomics and metabolomics (UHPLC-MS/MS); biotechnological methods: heterologous protein expression, bioleaching. MORE INFORMATION: https://www.orion.sci.muni.cz/cs/veda-a-vyzkum/vyzkumna-skupina-environmentalni-biotechnologie.html

Poznámky

Školitelem této práce bude dr. Kučera po schválení Vědeckou radou PřF MU.

Školitel

Mgr. Jiří Kučera, Ph.D.

We analyze hundreds of single enzyme molecules in parallel using arrays consisting of 50 000 very small (40 femtoliters) reaction chambers. Individual enzyme molecules have been observed by fluorescence microscopy to possess discrete and different turnover rates due to different molecular conformations (1-3). For example, the activity of beta-galactosidase is broadly distributed in an enzyme population.
We recently designed the first photo-switchable inhibitor for beta-galactosidase (4). With this inhibitor, we will investigate how the activity of single enzyme molecules can be switched on and off on demand by light. This mechansims will then be exploited to control the initiation of subsequent processes.

Profile: High motivation and joy in working on new experimental approaches in biochemistry/biophysics. Willingness to use English communication in an international team.

We offer: Supportive environment for interdisciplinary work in an international team. Work on state-of-the-art projects. Building an international network.

Literature:
(1) Gorris HH, Rissin DM, Walt DR (2009): Stochastic inhibitor release and binding from single-enzyme molecules. PNAS 104 (45) 17680-17685.
Rissin DM, Gorris HH, Walt DR (2008): Distinct and long-lived activity states of single enzyme molecules. J. Am. Chem. Soc. 130 (15) 5349-5353.
(2) Gorris HH, Walt DR (2009): Mechanistic aspects of horseradish peroxidase elucidated through single-molecule studies. J. Am. Chem. Soc. 131 (17) 6277-6282.
(3) Liebherr RB, Renner M, Gorris HH (2014): A single molecule perspective on the functional diversity of in vitro evolved beta-glucuronidase. J. Am. Chem. Soc. 136 (16) 5949-5955.
(4) Rustler K, Mickert MJ, Nazet J, Merkl R, Gorris HH, König B (2019): Development of photoswitchable inhibitors for beta-galactosidase. Org. Biomol. Chem. 16 (40) 7430-7437

Školitel

Dr. rer. nat. Hans-Heiner Gorris

BACKGROUND: Renal cell carcinoma (RCC) represents a serious oncological disease with the highest incidence in the Czech Republic. The reliable molecular markers related to the critical clinical scenarios are still missing.

FOCUS: We use a novel mass spectrometry technique in data independent acquisition mode to acquire digital fingerprints or a well-characterized set of RCC tumors collected accross the Czech Republic. We aim to identify protein markers or patterns relevant for the clinical scenarios in question, characterize these markers functionally, modulate them therapeutically, and validate.

EXAMPLE of potential doctoral project - the student will focus on:
*Protein biomarkers and patterns identifying patients with localized RCC with a high risk of relapse
*Protein biomarkers and patterns identifying patients with metastatic RCC with a high risk of poor response to available therapy
*Functional characterization of identified proteins using CRISPR/Cas9 technique followed by analysis of cell migration, invasiveness and sensitivity to potential inhibitors.
*Development of a targeted mass spectrometry method for a routine quantification of the novel marker proteins.
We expect that the identified potential biomarkers, therapy targets or molecular patterns will contribute to a more efficient treatment of RCC patients. Supported by Ministry of Health of the Czech Republic, project NV19-08-00250. In the later phase of the study, this concept can be extended to further solid malignancies such as colorectal cancer and breast cancer.

METHODS Liquid chromatography-mass spectrometry, data analysis, molecular and cellular biology, CRISPR/Cas9, analysis of cell migration and invasion
MORE INFORMATION: http://www1.sci.muni.cz/en/UBCH/Proteomika

PLEASE NOTE: Before initiating the formal application process to doctoral studies, the candidate is required to contact Doc. Pavel Bouchal for informal discussion.

Školitel

doc. Mgr. Pavel Bouchal, Ph.D.

BACKGROUND: Modern methods of crop protection aim to reduce the pesticide application and their presence in food and environment. Precise monitoring of the pathogen pressure and, if possible, the crop resistance is necessary to prevent superfluous pesticide application.
FOCUS: The group is focused on finding metabolic markers of crop defensive power. We will monitor the pathogen presence and crop disease symptoms in the field as well as the levels of potential metabolic markers of defence in the crop plants during the season.
EXAMPLES of potential student doctoral projects: Monitoring of defence-hormones levels; Expression analysis of defence-related genes; Targeted and untargeted metabolomics of healthy and diseased plants; Quantification of specialized metabolites.
METHODS: PCR, LC/MS, basic biochemical methods
MORE INFORMATION: https://www.orion.sci.muni.cz/cs/veda-a-vyzkum/vyzkumna-skupina-sekundarni-metabolity.html
PLEASE NOTE: Before initiating the formal application process to doctoral studies, the candidate is required to contact Katerina Dadakova for an informal discussion.

Poznámky

Školitelkou této práce bude paní dr. Dadáková po schválení Vědeckou radou PřF MU.

Školitel

Mgr. Kateřina Dadáková, Ph.D.

Alzheimerova choroba vzniká jako důsledek více faktorů, mezi které patří faktory životního stylu, ale také genetické faktory. Mírná kognitivní porucha (MKP) je heterogenní klinická jednotka, u které se rozeznávají dvě formy, a to amnestická forma mírné kognitivní poruchy, kdy dochází k objektivní poruše paměti a neamnestická forma mírné kognitivní poruchy. Amnestická forma MKP je charakterizována poruchou paměti, případně postižením dalších kognitivních funkcí, které však nedosahují úrovně demence. Udává se, že tato forma přechází do Alzheimerovy choroby ve 12-18% za rok.
V rámci disertační práce budou sledováni a vyšetřováni pacienti s Alzheimerovou chorobou a s amnestickou formou MKP s cílem zjistit, zda některé genetické markery, které souvisejí s Alzheimerovou chorobou, nejsou přítomny u MKP, což by mohlo v budoucnu přispět k časnému záchytu rizikových osob. Doktorand bude v rámci své práce izolovat DNA ze vzorků pacientů. Pro genotypizace minimálně 400 probandů bude použita metoda NGS sekvenování a kapilárního sekvenování. Jedním z cílů disertační práce bude také porovnávání vlastností buněčných kultur získaných z fibroblastů pacientů s Alzheimerovou chorobou. Zkoumány budou např. rozdíly transkriptomu. Výsledná data budou statisticky analyzována a budou začleněna do stávajícího modelu patogeneze Alzheimerovy choroby.

Školitel

prof. RNDr. Omar Šerý, Ph.D.

OBJECTIVES: With the intention to better understand the effects, which may play an important role in the biological (pharmacological) action of new combinations of anticancer metallodrugs and agents capable of targeting mechanisms connected with resistance of tumor cells to metallodrugs, new, “dual or multi-action” combinations of chemotherapeutics having the genes that confer resistance to anticancer drugs (cancer resistome) as one of the targets of their action will be introduced and tested. New combinations of metallodrugs and molecules targeting cancer resistomes capable of dual targeting of resistance mechanisms and at the same time DNA will be developed; detailed studies of cytotoxicity, selective targeting into tumor cells, inactivation by coordination to sulfur-containing proteins, DNA binding, cell accumulation, efficiency to affect DNA repair, tolerance of the resulting DNA damage, cellular responses and signaling pathways of new combinations will be performed. To achieve these goals, modern methods of biochemistry, molecular biophysics, oncology, and cell pharmacology will be used.

FOCUS: The aim of this research is to address the need for new combinations of chemotherapeutics capable of targeting mechanisms connected with the resistance of tumor cells to anticancer drugs. The identification of such combinations will improve the efficiency of drugs to kill tumor cells. These studies will be performed using modern biochemical methods and methods of molecular and cellular biophysics available at the Department of Molecular Biophysics and Pharmacology of the Institute of Biophysics, Czech Academy of Sciences in Brno.

EXAMPLES of potential student doctoral projects:

• Targeting resistance to chemotherapy of tumor cells to reinstate their susceptibility to novel, existing and unsuccessful anticancer metallodrugs
• Nanocarriers co-encapsulating two or multiple therapeutic agents
• Synergistic effects of polypharmacology involving metallodrugs in combination with other drugs capable of targeting cancer resistome

MORE INFORMATION: https://www.ibp.cz/en/research/departments/molecular-biophysics-and-pharmacology/info-about-the-department

Školitel

prof. RNDr. Jana Kašpárková, Ph.D.

V průběhu roku 2020 byl svět zachvácen pandemií virem SARS-CoV-2, která pokračuje i v roce 2021. První případy onemocnění COVID-19, způsobených virem SARS-CoV-2 jsou popsány na tržišti s divokými zvířaty ve Wuchanu. Pacienti trpěli závažnými respiračními infekcemi doprovázenými dalšími příznaky, jako jsou horečky, zánět plic, kašel, dušnost, průjmy atd. Analýzou sekvence RNA viru se ukázalo, že se jedná o zatím nepopsaný druh koronaviru, který je příbuzný virům SARS a MERS. Virus rozšířil po celém světě a do konce dubna 2021 způsobil úmrtí více než 3 milionů lidí. Většina osob, které umírají, jsou osoby nad 60 let věku. Nové varianty koronaviru ale způsobují úmrtí i mladších osob a nevyhýbají se bohužel ani těhotným matkám.
Cílem disertační práce bude analyzovat vzorky získané z těl osob, které byly nakaženy koronavirem SARS-CoV-2. Bude zkoumána přítomnost virů v různých tkáních a orgánech metodou RealTime PCR, mikroskopickými a imunologickými technikami. Tkáně budou vyšetřovány mikroskopickými technikami v souvislosti se strukturálními změnami vzniklými onemocněním COVID-19. Bude zkoumána genová exprese vybraných genů v odebraných vzorcích. Výsledná data budou statisticky zpracována, vyhodnocena a začleněna do aktuálních poznatků o patogenezi onemocnění COVID-19.

Školitel

prof. RNDr. Omar Šerý, Ph.D.

BACKGROUND: Triple negative breast cancer (TNBC) appears as a homogenous group within a current breast cancer (BC) classification based on hormonal and Her-2 receptors. It is typically treated using chemotherapy. Based on gene expression classification, however, this is a molecularly heterogeneous subtype that can be classified into several sub-subtypes.
FOCUS: We will (i) classify the well characterized set of ca. 100 TNBC tumors into sub-subtypes based on proteotypes obtained using data independent acquisition mass spectrometry, (ii) differences between transcriptomics (RNA-Seq) and proteomics profiles will be characterized and gene products typical for protein level will be identified, and (iii) impact of somatic mutations on levels of key proteins identified in proteotypes will be analyzed. We will aim to identify proteins, molecular pathways and mutations critical for TNBC proteotype classification that associate with therapy response, patient survival and could serve as targets of stratified TNBC treatment.
EXAMPLE of potential doctoral project - the student will focus on:
*Protein and transcript biomarkers, gene mutations and patterns typical of TNBC subtypes.
*Functional characterization of identified proteins using CRISPR/Cas9 technique followed by analysis of cell migration, invasiveness and sensitivity to potential inhibitors.
*Development of a targeted mass spectrometry method for a routine quantification of the novel marker proteins.
*The student will be involved in a collaboration with local and international research team members to analyze and intepret associations between gene mutations, transcript and protein levels.
METHODS: Liquid chromatography-mass spectrometry, RNA-Seq, exome sequencing, proteomics, data analysis, molecular and cellular biology, CRISPR/Cas9, analysis of cell migration and invasion.
MORE INFORMATION:
Supported by Ministry of Health of the Czech Republic, project NU22-08-00230 (2022-25). https://www.muni.cz/vyzkum/projekty/65540
https://www.orion.sci.muni.cz/cs/veda-a-vyzkum/vyzkumna-skupina-proteomiky.html
PLEASE NOTE: Before initiating the formal application process to doctoral studies, the candidate is required to contact Doc. Pavel Bouchal for informal discussion.

Školitel

doc. Mgr. Pavel Bouchal, Ph.D.

Lectins are ubiquitous carbohydrate-binding proteins, which play a key role in various processes including cell-cell communication and host-pathogen interaction, but also serve as a valuable tool for medicine and life sciences research. Carbohydrate-mediated recognition plays an important role in the ability of pathogenic bacteria to adhere to the surface of the host cell in the first step of their invasion and infectivity. Lectin-carbohydrate interactions are usually characterised by a low affinity for monovalent ligands that is balanced by multivalency resulting in high avidity for complex glycans or cell surfaces.
The main aim of the PhD work will be the structure-functional studies of carbohydrate binding proteins involved in a bacterial pathogenesis and/or their application as the bioanalytical tool to study a specific glycosylation related to cell specific tissues.

Školitel

prof. RNDr. Michaela Wimmerová, Ph.D.