Human Apoliproprotein E (ApoE) is a 299 amino acid glycoprotein involved in the lipid and cholesterol transport, which is also involved in multiple neurodegenerative diseases. One of these pathologies is Alzheimer’s disease (AD), a progressive neurodegenerative disorder characterised by the formation of amyloid plaques in the brain. Amyloid plaques consist primarily of a 40-42 amino acid-long peptide called beta-amyloid. The imbalance between the production and clearance of Aß is widely believed to be a trigger of AD pathogenesis. The clearance of Aß in the brain is regulated by ApoE. The three isoforms of ApoE (ApoE2, ApoE3, and ApoE4) bind to Aß with different affinities and therefore influences Aß clearance to a different extent. While ApoE2 appears to be protective, and ApoE3, the most common isoform in the human population is considered neutral, ApoE4 is considered the most prevalent genetic risk factor for sporadic late-onset AD. Therefore, ApoE represents a potentially attractive diagnostic and therapeutic target for AD. However, despite extensive research on the ApoE, our understanding of its biologically favoured structural organization and complexation remains elusive. In this project, we will therefore conduct detailed biophysical, biochemical, and structural analysis of ApoE isoforms to decipher the molecular basis of its native oligomerization as well as its pathological aggregation. Moreover, we will employ chemical biology approaches to explore how pathological ApoE aggregation might be prevented via drug-like small-molecule correctors, providing insights that will guide future drug discovery efforts.

Poznámky

téma je rezervováno pro Anetu Vaškovou

Školitel

Ing. RNDr. Martin Marek, Ph.D.

Aims: The aim of the thesis is to build a framework for estimating effects of xenobiotics on human microbiome metabolic pathways.

Background and methods: Food with its variety of dietary compounds, environmental chemicals, pollutants, as well as medications can be considered as xenobiotics to the human microbiome. In homeostasis (the healthy state that is maintained by the constant adjustment of biochemical and physiological pathways), human microbiome provides an extra set of biochemical reactions. The intrusion of xenobiotics has the potential to introduce a departure from homeostasis in many ways seen from the perspective of human microbiome, but both human cells and microbial communities living in their surroundings have to cope with these perturbations: pollutants can trigger latent enzymatic activities changing the functional potential of these microbial consortia; other drug metabolites can block important enzymes or can be biotransformed making antibiotics or other medical interventions useless or ineffective. Such perturbations (blocks and diversions of normal enzymatic activities) can be modeled and explored in the context of metabolic network models. Computational System Biology approaches can model and explore consequences of changes in the structure of networks simulated by random or target attack to nodes/metabolites in the metabolic network of the microbiome of interest. The assembled metabolic network model for the community understudy will be dynamically “updated” based on selected computational approaches aimed at predicting latent enzymatic activities (edge insertion update), enzymatic inhibition (edge deletion update), or changes in kinetics (edge weight update).

Školitel

Mgr. Eva Budinská, Ph.D.

Neurological disorders present a fundamental problem to our society as the second leading cause of death and the biggest cause of disability. Absence of effective treatment and ageing structure of population are potentiating this problem. The goal of this work is using molecular simulations and bioinformatics analyses in the study of etiology, pathogenesis, and treatment of neurological diseases, especially stroke and Alzheimer‘s disease. The methods of molecular dynamics and its advanced techniques as adaptive sampling, metadynamics, and metainterference will be used together with bioinformatics analyses of sequence databases. These computational methods will be used to study the phenomena behind neurological diseases and design of new molecules for their diagnostics and therapy. The result of this work will be the knowledge of structural-biological background of etiopathogenesis and therapy of neurological disorders and design of new medicines and treatment strategies.

Poznámky

Tema rezervovane pro Jan Micana

Školitel

Mgr. David Bednář, Ph.D.

Cílem práce bude studium enzymů pomocí výpočetních metod molekulového modelování a bioinformatiky. Výstupem analýz budou nejen nové poznatky v enzymologii, ale také varianty enzymů vytvořené metodami proteinového inženýrství, které budou mít potenciál v biotechnologických či biomedicínských aplikacích. Analýzy i design nových variant se zaměří na vylepšování stability molekul, které budou studovány metodami jako je Rosetta, FoldX nebo FireProt. Dále bude studována a optimalizována aktivita, specificita a selektivita enzymů metodami molekulového dokování, molekulové dynamiky, kvantová chemie a dalších. Poznatky ze studia enzymů budou také využity pro zlepšování softwarových nástrojů k analýze a designu proteinů, které tým v Loschmidtových laboratořích dlouhodobě vyvíjí.

The aim of this thesis will be to study enzymes by in silico approaches of molecular modeling and bioinformatics. The outcomes of the project will be used both in understanding the basics of enzymology and also to design enzyme variants by methods of protein engineering which can be applicable in biotechnology or biomedicine. The analysis and design of new enzyme variants will focus on improving the protein stability by methods like Rosetta, FoldX, or FireProt. Morover, other enzyme properties like activity, selectivity, or specificity will be analysed and optimized by molecular docking, molecular dynamics, or quantum chemistry calculations. The knowledge obtained during the analysis and design of enzymes will be utilized to improve functionality of software tools for protein engineering which are developed in Loschmidt laboratories.

Školitel

Mgr. David Bednář, Ph.D.

The recent advancements of Machine Learning (ML) techniques, coupled with growing protein data, provide promising directions for protein engineering. There are three types of protein data with an excellent ML potential: (i) in silico simulations, (ii) experimental measurements, and (iii) databases of protein sequences and structures. While ML has already leveraged some data from all the three sources in various applications in protein engineering, the field has only recently emerged, and much data remain unexplored. This project aims to explore the potential of machine learning methods in collecting protein data, reducing its dimensionality, performing data analysis, prediction, and optimization, to produce designs of improved proteins. The impact will primarily be (i) the new knowledge of the underlying mechanisms, (ii) promising protein variants, and (iii) user-friendly software tools that will provide access to the developed algorithms to the broader community of protein engineers.

Školitel

Stanislav Mazurenko, PhD

OBJECTIVES: The research aims to explore mechanisms (molecular toxicology, biomarkers of effects, toxicogenomic responses) triggered in humans and natural biota by organic pollutants, their metabolites and mixtures. The outcomes contribute to protection of the environment and health by providing scientific evidence and support to pragmatic risk assessment and management of chemicals.

FOCUS: Doctoral research projects focus on the effects of chemical groups that are broadly used in practice but their (eco)toxicological characterization is poor such as novel types of flame retardants, pharmaceuticals, pesticides and other potential endocrine-disrupters. Students benefit from outstanding research facilities of RECETOX that include high-end analytical instrumentations, molecular toxicology laboratories, alternative toxicological models - aquatic invertebrates and zebrafish.

EXAMPLES of potential student doctoral projects:
* Development of quantitative Adverse Outcome Pathways (AOPs) for liver toxicity and obesogenicity
* AOP networks beyond the male reproductive disorders
* In vitro toxicological investigations of novel flame retardants
* Molecular and biochemical effect biomarkers of low-dose mixture exposures in human cohort samples
* Automated text-mining approaches integrating toxicological data to toxicological knowledge

MORE INFORMATION: www.recetox.muni.cz

PLEASE NOTE: before initiating the formal application process to doctoral studies, all interested candidates are required to contact Prof. Ludek Blaha (blaha@sci.muni.cz) for informal discussion.

Školitel

prof. RNDr. Luděk Bláha, Ph.D.

The advertised positions will focus on environmental epidemiology. The successful candidates will investigate associations between environmental and social stressors and population health in the extensive prospective cohort studies (CELSPAC, HAPIEE) in the Czech Republic using multivariable regression techniques.

The selected Ph.D. students will join a newly established ERA Chair Team (https://www.recetox.muni.cz/erachair) supported by the competitive Horizon 2020 ERA Chair project R-EXPOSOME.

Školitel

Mgr. Hynek Pikhart, Ph.D., M.Sc.

Alzheimerova choroba je nejběžnější příčinou demence (60-80% případů) u starší populace po celém světě. Současný výzkum podporuje myšlenku, že agregace bílkovin iniciuje nástup Alzheimerovy choroby. Navzdory velkému množství dostupné literatury a studií zůstává mechanismus patogeneze a potenciální léčba Alzheimerovy choroby nejasný. Cílem disertační práce je aplikovat moderní a vysoce specifické analytické techniky (ultra-účinná kapalinová chromatografie - UHPLC a tandemová hmotnostní spektrometrie – MS/MS) ke kvantitativnímu profilování biomarkerů, které jsou spojovány se vznikem této lidské neuropatologii. Konkrétně půjde o aplikaci cílených instrumentálních technik hmotnostní spektrometrie (např. selected reaction monitoring – SRM) a jejich využití ke kvantitativní charakterizaci složení membránových lipidů a proteinů v biologických vzorcích. Očekávaným výstupem jsou informace o změnách hladin jednotlivých tříd lipidů a proteinů v biologických membránách a sledování případných biologických a klinických důsledků těchto změn.

Alzheimer's disease is the most common cause of dementia (60-80% of cases) in the elderly population around the world. Current research supports the idea that protein aggregation initiates the onset of Alzheimer's disease. Despite a large number of available literature and studies, the mechanism of pathogenesis and the potential treatment for Alzheimer's disease remain elusive. The dissertation thesis aims to apply modern and highly specific analytical techniques (ultra-high performance liquid chromatography - UHPLC and tandem mass spectrometry - MS/MS) for the quantitative profiling of biomarkers associated with the development of human neuropathology. Specifically, the application of targeted instrumental techniques of mass spectrometry (i.e., selected reaction monitoring - SRM) will be used to quantitatively characterize the composition of membrane lipids and proteins in biological samples. The expected output is information on changes in individual lipid classes and protein levels in biological membranes and monitoring of potential biological or clinical consequences of these changes.

Školitel

PharmDr. Zdeněk Spáčil, Ph.D.

Práce se bude zaměřovat na nové přístupy hodnocení vlivu vybraných faktorů exposomu na biomarkery efektu a možná zdravotní rizika v lidské populaci. Hodnoceny budou například vybrané skupiny chemických látek a stresorů, které byly prioritizovány v rámci mezinárodního projektu HBM4EU. Důraz bude kladen také na statistické metody hodnocení. Do analýz budou zahrnuta jak data o externí expozici chemickým směsím, tak i výsledky analýz biomarkerů efektu. Metody budou aplikovány na reálná data získaná z kohortových studií (například CELSPAC – FIREexpo, CELSPAC-YA, atd.), ale také i z populačních dat.
Detaily o tomto Ph.D. výzkumném zaměření budou sděleny při osobní konzultaci - doc. RNDr. Pavel Čupr, Ph.D. (cupr@recetox.muni.cz). Zaměření odborné skupiny je popsáno zde - WEB: https://www.recetox.muni.cz/hear
Před výběrem výzkumného zaměření mne prosím kontaktujte: pavel.cupr@recetox.muni.cz.

Školitel

doc. RNDr. Pavel Čupr, Ph.D.

Chemical contamination in indoor environments contains a wide range of chemicals emitted by indoor objects, materials or indoor human activities and can pose a risk to aquatic ecosystems when the chemicals enter the water cycle. This PhD project will investigate aromatic amines (AAs), which are hypothesized to be emitted from indoor environments and significantly contribute to the total burden of mutagenicity in surface waters. Laundered textiles contaminated with AAs by indoor emission sources are hypothesized to act as a vector of these substances to wastewaters, but this pathway is not well understood. Investigation of this pathway will help us understand better the occurrence of AAs in surface waters. AAs originate from indoor human activities like tobacco smoking and grilling meat. They can adsorb to textiles via gaseous sorption or accumulation of particles such as house dust or aerosols. This project will focus on understanding the uptake of aromatic amines on textiles through air and particle adhesion and their distribution in indoor environments via laboratory and field-based textile exposure experiments, and multi-media environmental monitoring of AAs in representative indoor environments.
The dissertation will be performed in collaboration with an international team of PhD students and senior researchers from Masaryk University, Brno and the Helmholtz Centre for Environmental Research, Leipzig, within the research project “Accumulation in textiles and release by laundry as an emission pathway for aromatic amines from indoor environments to waste- and surface water” funded by Czech Science Foundation (GAČR) and the German Research Foundation (DFG).

Školitel

Lisa Emily Melymuk, Ph.D.

Miniaturization and automation are key trends in modern experimental methods in the natural sciences and biomedicine. Microfluidics makes it possible to perform thousands of experiments per second thanks to the precise handling of nano- to pico-liter volumes of solutions in the microenvironment of channels measuring tens of micrometers. The project will focus on the development and optimization of microfluidic systems for high-performance characterization and study of proteins obtained from genomic databases and constructed by protein engineering methods. The obtained data will be evaluated by artificial intelligence methods. The newly developed methods will be applied in the study of the mechanism of Alzheimer's disease and the development of new drugs for stroke. The project will be solved in cooperation with the research group Prof. Andrew deMello at ETH Zurich, Switzerland (https://www.demellogroup.ethz.ch/) and the International Center for Clinical Research, University Hospital at St. Anny in Brno

Školitel

prof. RNDr. Zbyněk Prokop, Ph.D.

Project summary: Enzymes catalyse most of the chemical reactions that occur in biological systems and can be given non-natural catalytic functions by protein engineering. However, despite their vast importance, we do not know how enzymes acquire the structural diversity and conformational flexibility that enables them to evolve towards new molecular functions. Our proof-of-concept data on three structurally similar but functionally distinct enzyme classes of haloalkane dehalogenases (EC 3.8.1.5), beta-lactone decarboxylases (EC 4.1.1.114), and light-emitting monooxygenases (EC 1.13.12.5) suggest that as-yet-underexplored molecular elements – access tunnels and flexible loops – play a pivotal role in their functional diversification.

The proposed PhD project will investigate the molecular structures of these model enzymes using an innovative multi-method biology approach to identify the key structural and dynamic elements that govern enzymes’ evolvability. This project will combine X-ray crystallography, single-particle cryo-electron microscopy, and advanced mass spectrometry techniques to capture unprecedented molecular details of the conformational sampling that is required for productive enzymatic biocatalysis. Complementary protein simulations, mutational and biochemical experiments will delineate the evolutionary trajectories that lead to the emergence of novel enzymatic functions. The resulting knowledge will extend our understanding of molecular evolution beyond the current state-of-the-art, particularly by revealing how the conformational diversity of proteins is associated with specific biocatalytic functions. The gained knowledge from this PhD project will pave the way for the development of new theoretical concepts and cutting-edge software tools for the rational engineering of tailor-made biocatalysts exploitable in biotechnology and biomedicine.

PLEASE NOTE: Before starting formal application/admission process, all applicants are requested to contact supervisor (martin.marek@recetox.muni.cz).

Školitel

Ing. RNDr. Martin Marek, Ph.D.

Urbanizace je tradičně spojována se stresem, úzkostí a duševními poruchami. Problematikou vztahu města a úzkosti se zabývá řada mezioborových projektů na pomezí neorubanizmu, který umožňuje řešit globální městské s využitím metod aplikovaných v neurologii. Existuje však pouze malé množství studií, které by využívaly aplikace biosenzorů k zachycení geolokalizovaných fyziologických markerů emočních reakcí na městské prostředí. Cílem dizertační práce je: 1) zpracovat podrobnou rešerši o vlivu urbánního prostředí na strukturu a funkci řady orgánových systémů a jejich interakce, 2) navrhnout vhodné metody pro sledování vybraných proměnných v podmínkách reálného života ve městě, 3) navrhnout a provést pilotní studii pro aplikaci biosenzorů měřících vhodné proměnné u modelové kohorty ve městě Brně, 4) translace poznatků do prostředí augmentované/virtuální reality a 5) provést modelování v AR/VR s cílem ovlivnit sledované proměnné.

Školitel

prof. MUDr. Julie Dobrovolná, Ph.D.