Education - Ph.D. studies - Institute of Biochemistry

Ph.D. Topics of the Institute of Biochemistry


Restoring vision, preventing blindness: search for drugs to inhibit pathological vascularisation of the retina (macula degeneration)

Group: Laboratory of Cytokine Research
Supervisor: Ernő DUDA

The human eye is a high precision optical instrument with exceptionally well organized cellular structure. The retina is a delicate tissue, which converts the light into images, and sends them to the brain. The macula is a small area at the very centre of the retina. The macula is allowing us to see colors and extremely fine details. In primates and man the photosensitive cells and the supporting layer of pigmented epithelial cells of the macula do not get oxygen from frontal blood vessels, only from the chorioid located beneath the basal membrane of the epithelial cells. Reduced oxygen supply – as the result of circulatory problems, accumulation of cellular debris between the chorioid and the epithelial cells, etc. – leads to hypoxia in the retina and might trigger growth of new capillaries into the macula. This “neovascularization” ultimately leads to bleeding, leaking and scarring from these blood vessels and eventually cause irreversible damage to the photoreceptors and rapid vision loss. Until recently, no effective treatments were known for macular degeneration. New anti-angiogenic monoclonal antibodies can cause regression of the abnormal blood vessels and improvement of vision when injected directly into the vitreous humor of the eye. The injections can be painful and frequently have to be repeated on a monthly basis. We want to develop painless, topical treatment for this crippling disease. Regulation of angiogenesis is a very complex phenomenon. We study the intricate balance of angiogenic and angiostatic molecules and we are working on the development of new combinations of peptides and small molecules that can penetrate the eye and target different events in the process of formation of new capillaries.


Synthetic biology: experimental validation of systems biology models of E. coli

Group: Laboratory of Genome Engineering
Supervisor: György PÓSFAI

Synthetic biology is the deliberate design of biological systems and living organisms using engineering principles. The long-term goal is the proper understanding of the cellular processes to create useful biological machines with programmable functions. We are focusing on the rational, large-scale remodeling of the genome of Escherichia coli K-12, a model organism of basic research, and the platform of choice for biotechnological applications. Systems biology models describe the working of the E. coli cell in ever increasing details, however, in spite of being one of the best understood organisms, the cell is still way too complex for reliable genetic programming. Our goal is to engineer reduced-complexity, core/minimal genome E. coli cells by experimental elimination of the genes irrelevant for laboratory applications. In the process of gradually streamlining the genome (Science 2006, 312: 1044-1046), we are investigating the effect of genome architecture and gene content on the adaptation and evolution of the cells, and compare experimental data with predictions of in silico models. The particular project for PhD students involves specific genetic modifications of wild-type and reduced E. coli genomes in order to validate and improve systems biology models of the cell.


G-protein kapcsolt neuroreceptorok: a dimerizáció celluláris- és molekuláris szintű kutatása (Elméleti Orvostudományok Doktori Iskola)

Group: Laboratory of Opioid Research / Chemical Biology
Supervisor: Sándor BENYHE

G-protein kapcsolt neuroreceptorok: a dimerizáció celluláris- és molekuláris szintű kutatása.


Opioid és antiopiát neuropeptidek: endogén agonisták és szintetikus analógok (Elméleti Orvostudományok Doktori Iskola)

Group: Laboratory of Opioid Research / Chemical Biology
Supervisor: Sándor BENYHE

Opioid és antiopiát neuropeptidek: endogén agonisták és szintetikus analógok funkcionális biokémiai kutatása


Natural combinatorial libraries for neuropeptides: evolution, structure-activity studies and biochemical characterization (Biológia Doktori Iskola)

Group: Laboratory of Opioid Research / Chemical Biology
Supervisor: Sándor BENYHE

Synthetic chemical peptide libraries, utilizing the combinatorial chemistry approach, have become powerful tools in identifying selective biomolecules. Apart from this progress, Darwinian natural selection, the impulsive force of the evolution, has also generated crowds of various bioactive compounds. The entire set of genomic data, particularly those sequences encoding for precursor polypeptides, represent remarkable chemical biodiversity at the level of mature oligopeptides, moreover provide comparative and comprehensive structural information for neuropeptide families. By screening public protein databases novel endogenous neuropeptide sequences will be identified (targeted neuropeptide families include opioid peptides, tachykinins and Neuropeptide FF analogues, — each involved in the regulation of pain percetion). Structures, endopeptidase recognition motifs, sequence frequency and similarity, evolutionary distances and phylogenetic trees will be analyzed by bioinformatic tools. Following bioinformatic analyses, a selection of substantial and quaint sequences will chemically be synthesized and studied also by biochemical means. One significance of these mutationally polymorph sequences is that they altogether compose a natural “combinatorial” library emerged by the evolution. The various peptides evolved by gene mutations offer template sequences for cell biological (receptor oligomerization and trafficking, signal transduction), moreover structure-bioactivity relationship studies investigated by receptor binding assays. As the mass of genome sequencing data grows rapidly, an increasing impact of the phylogenetic and bioinformatic studies on experimental biology is expected.


Evolution of sequence recognition by Type II restriction– modification systems

Group: Laboratory of DNA-Protein Interaction
Supervisor: Antal KISS

Type II restriction-modification systems (R-M systems) consist of a sequence specific endonuclease (restriction endonuclease, REase) and a sequence specific modification DNA methyltransferase (MTase), which recognize the same target sequence on double-stranded DNA. The REase cuts the DNA at unmodified target sites, whereas the MTase modifies these sites by methylating an adenine or cytosine in each strand of the recognition sequence. The specific methylation protects the target sites against the cognate REase and is therefore critical for the viability of the bacterium producing the REase. It has been shown for a number of R-M systems that the REase and the MTase of the same system have similar levels of specificity (Brooks and Roberts, Nucleic Acids Res. 10: 913-934, 1982). This is surprising because a MTase with lower specificity would provide the added safety of also methylating some of the sites, which differ from the canonical target sequence by one nucleotide and which can be occasionally cut by the REase. For example, an R-M system consisting of a GAATTC-specific REase and an AATT-specific MTase should be functional. Yet, no natural R-M system characterized by a MTase displying substantially lower specificity than the counterpart REase is known. Apparently, during evolution of R-M systems there is a pressure to fine-tune specificities of the two enzymes to similar levels. It is not known why matching specificities are optimal and what mechanisms are responsible for evolving and maintaining the specifities of R-M systems. We wish to study this phenomenon by constructing strains that carry, inserted into the genomic DNA, artificial R-M systems in which the MTase has lower specificity than the REase. Fitness of the strains under different growth conditions and their capacity to restrict bacteriophage infection will be studied and compared with strains carrying RM systems of matching specificity. Spontaneous and induced mutations leading to changes in the specificity of the enzymes will be isolated and their effects on fitness of the bacterium will be investigated. Interesting mutant enzymes will be characterized in vivo and in vitro. These studies will be carried out in close collaboration with the laboratories of György Pósfai and Csaba Pál in the Institute of Biochemistry of the BRC.


Poszt-transzlációs módosítások vizsgálata tömegspektrometriával.

Group: Laboratory of Proteomics Research
Supervisor: Katalin MEDZIHRADSZKY

A szekretált fehérjék és a membránfehérjék extracelluláris szakaszának gyakori poszttranszlációs módosítása a glikoziláció. Citoszolikus és magi fehérjék szintén lehetnek glikoziláltak. Míg az N-glikozilációt (a glikziláció Asn-oldalláncon történik) kiterjedten vizsgálják, az O-glikozilációról (Ser/Thr-hoz kötött módosítás) sokkal kevesebbet tudunk.
A projekt célja O-glikoproteinek és –peptidek szelektív izolálása és tömegspektrometriás jellemzése komplex mintákból.


A szimbiotikus gyökérgümő kialakulásában szerepet játszó peptidek és fehérjék tömegspektrometriás vizsgálata

Group: Laboratory of Proteomics Research
Supervisor: Katalin MEDZIHRADSZKY

A nitrogénkötő baktériumok terminális differenciációjában szerepet játszó gümőspecifikus antimikrobiális peptidek izolálása, szeparálása és tömegspektrometriás jellemzése. A differenciálódó és érett bakteroidok peptidkészletének tömegspektrometriás jellemzése. A gümőspecifikus peptidekkel kölcsönható fehérjék azonosítása tömegspektrometria segítségével.


Gyógyszerkölcsönhatások rendszerbiológiája és bioinformatikája

Group: Laboratory of Evolutionary Systems Biology
Supervisor: Balázs PAPP

Az antimikrobiális szerek ellen kialakuló rezisztencia fokozódó kihívást jelent az egészségügy számára. Amellett, hogy a gyógyszeripar újabb hatóanyagok kifejlesztésén fáradozik, egyre inkább szerepet kap a már meglévő szerek olyan újszerű kombinációinak (ún. „hatóanyagkoktélok”) a megtalálása, amelyek hatásosak akár a rezisztens törzsekkel szemben is. A szinergisztikus (egymást erősítő) kölcsönhatást mutató hatóanyagok kísérletes azonosítása azonban komoly kihívást jelent a lehetséges kettes, hármas, stb. gyógyszerkombinációk csillagászati száma miatt. E problémából kiutat jelenthetnek olyan adatbányászati és statisztikai eljárások, amelyek képesek lennének nagy megbízhatósággal előrejelezni korábban nem vizsgált gyógyszerkombinációk közötti erősítő avagy gyengítő kölcsönhatásokat is. Jelen munka célja, hogy meglévő, irodalomban közölt, illetve kollaboránsunk laboratórumában megmért antibiotikum kölcsönhatásokra alapozva olyan kemogenomikai és funkcionális genomikai prediktorokat azonosítsuk amelyek segítségével jósolni tudjuk új antibiotikumkombinációk hatását. A vizsgált modellszervezet az E. coli lesz, melyre nagyszámű biokémiai (pl. anyagcsereútvonalak), funkcionális genomikai (pl. fehérjék közötti fizikai kapcsolatok) és kemogenomikai (pl. génkiütés hatása egyes antibiotikumokkal szembeni rezisztenciára) információ áll rendelkezésre, így a gyógyszermolekulák célpontgénjeink kapcsolatrendszere segítségével írhatjuk le a gyógyszerkölcsönhatásokat. A számítógépes jóslatokat együttműködés keretében a Pál labor kísérletesen is ellenőrzi. Távolabbi célunk, hogy ne csak a vad típusú törzs ellen hatékony antibiotikumkombinációkat tárjunk fel, hanem olyan új kombinációkat is, amelyek az egyedi hatóanyagokkal szemben rezisztens törzsek növekedését is képesek gátolni. A témára programozásban és elemi statisztikai vizsgálatokban jártas jelentkezőket várunk.


Fehérjeszármazékok előállítása szerkezeti és funkcionális vizsgálatok céljára (Elméleti Orvostudományok Doktori Iskola)

Group: Laboratory of Opioid Research / Chemical Biology
Supervisor: Csaba TÖMBÖLY

Az élő szervezetek számára kulcs-fontosságú, hogy a genetikailag kódolt több tízezer különböző fehérjemolekula a megfelelő helyen, a megfelelő időben és megfelelő kémiai szerkezettel rendelkezésre álljon. Amennyiben sérül ez a komplex rendszer, valamilyen kóros elváltozást tapasztalunk. Egy ilyen nem megfelelő fiziológiás állapot korai detektálásához, valamint hatékony kezeléséhez ismernünk kell a folyamatot befolyásoló fehérjemolekulák szerkezetét és funkcióját. Félkémiai módszerek alkalmazásával bővíthető a rekombináns úton előállítható fehérje származékok köre, így megváltoztathatjuk a fehérje biokémiai viselkedését, valamint új funkciós csoportok, fluoreszcens és izotópos jelek bevitelével növelhetjük kémiai információtartalmát. Kutatásaink során a fehérjék széles körére alkalmazható, fiziológiás körülmények között is magas specificitást mutató reakciókat vizsgálunk, melyek lehetővé teszik a specifikusan módosított célfehérje szintézisét szintetikus peptid és nem-peptid, valamint rekombináns fehérje elemekből. Végső soron szerkezet-funkció összefüggések szisztematikus tanulmányozása, valamint a fehérjék tulajdonságainak tervezhető hangolása válik lehetővé.


Fehérjék módosítása kémiai módszerekkel (Kémia Doktori Iskola)

Group: Laboratory of Opioid Research / Chemical Biology
Supervisor: Csaba TÖMBÖLY

A genom szekvenálások sikeres lezárásával párhuzamosan nő az igény olyan speciális fehérjeszármazékok iránt, amelyek széleskörű finomszerkezeti és funkcionális vizsgálatokat tesznek lehetővé. A fehérjemolekulák kovalens szerkezetének módosításával megváltoztathatjuk a fehérje biokémiai viselkedését, valamint új funkciós csoportok, fluoreszcens és izotópos jelek bevitelével növelhetjük kémiai információtartalmát. Az ismert kémiai módszerek általános alkalmazhatóságának azonban gátat szab, hogy a fehérjék funkcióihoz szükséges három-dimenziós szerkezetek környezeti hatásokra általában érzékenyek. Kutatásaink során a fehérjék széles körére alkalmazható, fiziológiás körülmények között is magas specificitást mutató kémiai reakciókat vizsgálunk, melyek lehetővé teszik a specifikusan módosított célfehérje szintézisét szintetikus peptid és nem-peptid, valamint rekombináns fehérje elemekből.


Studies on the mechanism of the conformational transition of the prion protein.

Group: Laboratory of Conformational Diseases
Supervisor: Ervin WELKER

Transmissible spongiform encephalopathies (TSE-s) are fatal neurodegenerative disorders of which primary symptoms usually include progressive dementia and ataxia, associated with spongiform degeneration of the brain and accumulation of an abnormal protease-resistant form of the prion protein (PrPres) in the central nervous system. Our aim is to understand the conformational transition of the protein to this abnormal isoform (PrPres).


The role of the prion protein in the progression of transmissible spongiform degenerations.

Group: Laboratory of Conformational Diseases
Supervisor: Ervin WELKER

Transmissible spongiform encephalopathies (TSE-s) are fatal neurodegenerative disorders of which primary symptoms usually include progressive dementia and ataxia, associated with spongiform degeneration of the brain and accumulation of an abnormal protease-resistant form of the prion protein (PrPres) in the central nervous system. Our aim is to discern how the formation of this abnormal form is associated with the neuronal cell death that is evident in this disease.


Quantitative structure-activity relationships methodology for flexible molecules: prediction, docking, database

Group: Laboratory of Opioid Research / Chemical Biology
Supervisor: Ferenc ÖTVÖS

Quantitative structure-activity relationships (QSAR) studies are of crucial importance in every stage of drug development, however, they are more and more wildly used in many different areas. The aim is to find a mathematical formula (the model) between the structure of chemical compounds and their biological effects (or other kind of properties) to make prediction for the effects of molecules not investigated yet. The first stage, the model building, relies on an appropriate description of the molecular structures and on a mathematical toolbox, namely the chemometrics branch of multivariate statistics. The most efficient chemometrics methods use some supervised learning algorithm to build a trained model using a set of selected molecules as training set. The model is then used to predict the same kind of properties for molecules not involved in the model building, named test set. The structure of the molecules is assessed by force field based molecular dynamics methods. The full description of the molecular structure should contain both the correct stereochemical features (chirality) and a possible statistical behaviour resulting from conformational flexibility, thus the use of extensive molecular modeling technics is vital. Furthermore, a special transformation of the molecular structures is developed to disregard the atomic connectivities in order to compare arbitrary molecular structures. Without this, only structurally related molecules can be involved a QSAR study. Fulfilling all these requirements results in a general molecular database for QSAR purposes.


Research Program: Role and regulation of extracellular matrix protein genes in health and disease

Group: Laboratory of Extracellular Matrix Biology
Supervisor: Ibolya KISS

Multicellular organisms deposit a highly organized extracellular matrix (ECM) around the cells, which provides physical support and the necessary milieu for normal cell metabolism and development, and delineates pathways during differentiation and tissue regeneration. The ECM performs essential, but very divergent functions in the various tissues and organs. We investigate how matrilins and other noncollagenous glycoproteins (e.g. cartilage link protein) involved in the organization of the ECM contribute to tissue integrity, differentiation and carcinogenesis using modern molecular biology methods, cell culture and transgenesis. In the framework of national and international collaborations, we study the influence of matrilin-2 deficiency on skeletal muscle regeneration, skeletal muscle and heart development, and induction of hepatocellular carcinoma. We are interested in the identification of signaling pathways, in which matrilin-2 is involved, including its interacting partners in the ECM and cell membrane. We also plan to investigate the expression of matrilin-2, other ECM proteins and Kir2.x ion channels in delated cardiomyopathy compared to non-diseased heart. We also investigate how the tissue-specific expression of matrilin genes is regulated in the developing musculo-skeletal system, focusing on the unique control mechanism restricting the matrilin-1 gene expression to distinct growth plate zones.


Role of matrilin-2 in skeletal muscle regeneration and in muscle differentiation

Group: Laboratory of Extracellular Matrix Biology
Supervisor: Ibolya KISS, Ferenc DEÁK

We observed transient increase in the matrilin-2 gene (Matn2) expression during notexin induced rat skeletal muscle regeneration. We are currently investigating the consequences of matrilin-2 deficiency on skeletal muscle regeneration in Matn2 knockout mice in collaboration with the laboratory of Prof. Dux László DSc. We also study myogenic differentiation in C2/7 myoblast cell line silenced in Matn2 using Sh RNA interference and following rescue. We plan to identify the signal transduction pathways disturbed in the absence of matrilin-2.


Role of matrilin-2 in tumor formation and testing the effect of anticancer drugs on hepatocarcinoma induction in matrilin-2 deficient mice

Group: Laboratory of Extracellular Matrix Biology
Supervisor: Ibolya KISS, Ferenc DEÁK

We observed increased hepatocarcinoma induction in Matn2 knockout mice in collaboration with the laboratory of Prof. Ilona Kovalszky DSc (Semmelweis University, Budapest). We study the molecular mechanism of tumor formation and the signaling pathways underlying the protective effect of matrilin-2 against tumor induction. We also utilize this transgenic animal model to study the effect of avinomids on hepatocarcinoma induction in collaboration with the laboratory of László Puskás DSc.


Dissecting the unique regulatory mechanism restricting the matrilin- 1 gene expression to distinct growth plate zones in transgenic mice.

Group: Laboratory of Extracellular Matrix Biology
Supervisor: Ibolya KISS

We have found that the matrilin-1 short promoter based on its interaction with homologous or heterologous upstream elements plays dominant role in determining the restricted cartilage-specific expression of the reporter gene in transgenic mice. We characterize the DNA elements and transcription factors involved in this unique regulation using a variety of in vitro assays (e.g. EMSA, supershift analysis, in vivo fooprinting) and in vivo techniques (transient expression, forced expression, transgenesis).


Expression of ECM molecules and ion channels in healthy and diseased myocardium

Group: Laboratory of Extracellular Matrix Biology
Supervisor: Ibolya KISS

We aim to investigate the expression and possible function of ECM molecules such as matrilin-2, fibronectin and collagens in healthy and diseased heart tissues. We also compare the differences in the amount and organization of potassium ion channels (Kir2.x) between healthy and diseased heart muscle using qRT/PCR, immunoblotting, immunofluorescence and immunoprecipitation in collaboration with the laboratory of Prof. András Varró DSc.


Mapping of the matrilin-2 functional domains in cell culture and in vivo

Group: Laboratory of Extracellular Matrix Biology
Supervisor: Ferenc DEÁK

Matrilin-2 is a constituent of the extracellular matrix in many organs. In cell culture it can be observed as part of a filamentous network. We aim to reveal the role of the protein domains in homo-oligomer formation and interaction with other ECM components and cell surface proteins.