Leader: Dr. Csaba Szalai, University professor
The Medical Genomics Research Group investigates the genomic and pharmacogenomic background and pathomechanism of the following multifactorial diseases: asthma, allergy and acute lymphoblastic leukemia. For our researches we use our asthma and childhood leukemia bio- and databanks, which are registered in the Hungarian NEKIFUT as strategic research infrastructures. In collaboration with the Department of Measurement and Information Systems of Budapest University of Technology and Economics, the group also participates in developing bioinformatic tools important for our researches.
Research projects of the group
Genetic analysis of susceptibility to childhood tumours and pharmacogenetic analysis of response to therapy
At the Department of Genetics, Cell- and Immunobiology there is a human data- and DNA biobank consists of DNA from 626 childhood acute lymphoblastic leukaemia (ALL), 93 childhood osteosarcoma and 70 testicle tumour patients and hundreds of healthy controls. In the databank we collected the patients clinical (medical and laboratory diagnostic) data at the diagnosis, and during the treatment until the end of the therapy. We recorded certain drug levels, side effects (regarding the cardiovascular system, nervous system, etc.) and in the case of some side effects follow up data after the treatment. Genetic polymorphisms in genes of drug metabolic enzymes, drug transporters and drug targets can influence the efficacy and even the effect of the medication. Gene polymorphisms can modify the necessary medicine amount for the optimal response and contribute to the development of side effects. In our research we study the relationship between the genetic polymorphisms of the above mentioned genes and the clinical data of the patients in our databank. We search for polymorphisms significantly influencing the response to therapy and the course of the disease. One group of these studied genes is the adenosine triphosphate binding casette (ABC) transporter superfamily. Several members of this superfamily are known to be expressed also in tumor cells and they are important in the transport of chemotherapic drugs across the cell membrane. Among these the best-known are the ABCB1 (ATP-binding cassette, sub-family B, member 1 or MDR1: multiple drug resistance 1) and ABCG2 (ATP-binding cassette, sub-family G, member 2), but many other genes involved in this process belong to ABC-transporters. The polymorphisms of thecytochrome p450 (CYP) gene family and different gene variants of other drug metabolic enzymes are also relevant in the chemotherapy treatment response. One of the most crucial aims of our research is to contribute to the new, relevant pharmacogenetic results of personalized therapy. Before finding the adequate therapy method, the physicians should determine the genotype of the patients to get a better outcome, and reduce the toxic side effects.
We also examine the inheritable susceptibility of tumourigenesis (ALL, osteosarcoma, testicle cancer). It is known, that in some family lines definite tumour incidence is more prevalent. It confirms that the susceptibility of disease development has genetic components too. The above-mentioned genes (e.g. ABCB1, ABCG2, CYP) have significant role in the transport ofxenobiotics, that can cause mutation in genes. The dysfunction of the MTHFR(member of the folic acid metabolic pathway), and GST (glutathione S-transferases, genes of redox system) gene family can also contribute to the development of the disease.
Genomic investigation of asthma with animal experiments and examinations of human samples
The asthma genetics research group conducts research to gain insight into the genetic background of asthma and the molecular biological patterns influencing the asthma pathomechanism by use of human samples and animal disease models. In these studies the group has succeeded in proving numerous genes, genetic variations and biological pathways contributing to the asthma phenotype.
Since 2006 due to our infrastructural development we are able to carry out high-throughput screenings, population genetic tests and microarrayexperiments to validate the SNP results.
Our Institute stores Hungary's largest asthma-allergy biobank which consists of clinical, laboratory data and DNA samples of 425 asthmatic, 304 allergic and 500 healthy children. In the future we aim to continuously enlarge our biobank by involving foreign samples also.
One of our scientific goals is the detailed mapping of genomic regions previously identified in asthma pathomechanism and the consequent genotyping of the newly identified polymorhisms on our biobank. Apart from the already characterized 11q13 region we plan to thoroughly investigate the genomic regions 14q22 and 17q1. Furthermore, we aim to analyze the polymorphisms of candidate genes identified by animal studies or literature data mining. The SNP searching and selecting procedure is directed by software developed by our group.
Our research group previously completed a whole genome gene expression microarray analysis (Agilent Whole Mouse Genome Oligo Microarray 44K chips were used) of OVA induced mouse model of asthma to follow the lung gene expression profile change in four state of the progression of mouse allergic airway inflammation. Microarray analysis revealed some new potential previously not investigated candidate genes which showed significantly changed gene expression profile during allergic progression. Out of these genes presently the study of paraoxonase 1 (PON1) is going on.
The examinations of human polymorphisms, selected genes from animal experiments and their role in asthma pathogenesis are carried out with the following protocol:
(I) Selection of genes according to the results of animal experiments. We favor previously not studied genes showing markedly changed gene expression during the disease progression.
(II) Identification of SNPs with bioinformatic methods and examination of their role with association studies on our biobank.
(III) Investigation of gene function on human samples. Experiments carry out according to known, revealed and supposed function of genes. Following studies are planning: gene and protein expression in lung (asthmatics vs. healthy subjects); enzyme activity in different samples and activity changes e.g. serum level during treatment; reveal the influencing factors (e.g. disease, smoking, age, drugs, treatment etc.) of gene and/or protein function
Our purpose with the above-mentioned examinations is to identify genes, genetic polymorphisms implicated in asthma pathomechanism or susceptibility. The realization of our aims could lead to the understanding of asthma development and further result in exploration of new therapy targets which could contribute to work out more effective and wide-ranging therapies for both patients and doctors.
Genetics of obesity
Obesity has become a major public health problem in most developed countries. According to some data 60% of the Hungarian population isoverweight or obese. It is well known that obesity is a risk factor for type 2 diabetes, dyslipidemia, hypertension, and atherosclerosis. The etiology of obesity is complex and consists of the interaction of genetics, diet and physical activity, additionally influenced by environmental, socioeconomic and behavioral factors. It is a metabolic disorder with energy balance disturbance, which is manifested in elevated nutrition or in decreased energy expenditure, and leads to fat accumulation. During the pathogenesis of obesity not only the fat storage increase but the size and number of adipose cells too.
Traditionally, adipose tissue was considered to passively store triacylglycerols and release free fatty acids, but it is now recognized as an active endocrine organ that produces a large number of bioactive mediators, which are interact with immune- and cardiovascular systems.
At the Department of Genetics, Cell- and Immunobiology we have examined the genetic background of obesity since 2007. The project is granted partly by ETT and partly by the NKTH, in which we participated as a member of the Obekon Consortium.
One of the most crucial aims of our research is to explain the pathogenesis of obesity by monitoring the DNA and transcriptional changing in human samples and animal models. In our research we study the genes influencing the pathomechanism of obesity, their polymorphisms, and the molecular disease pathways.
Developing Bioinformatics Tools
The Department of Genetics, Cell- and Immunobiology (DGCI) at Semmelweis University cooperates with Department of Measurement and Information Systems (DMIS) at Budapest University of Technology and Economics since 2005. The colleagues of the two departments work together on developing various bioinformatics methods that can accelerate the disease specific (e.g. asthma, acute lymphoblastic leukaemia, childhood tumors) genetic research in DGCI.
The bioinformatics tools and methods developed at DMIS can be utilized in two main areas: (i) they help in the economical designing of the investigations of the genomics laboratory so the investigations on the available samples should provide the most information with the least possible cost. (ii) On the other hand the exhaustive evaluation of the datasets provided by the genetic investigations and the design of further genetic investigations based on that information need complex bioinformatics apparatus.
The inter-individual difference in genetic background between two patients can considerably influence the effects of specific treatments. Identifyingbiomarkers connected with the expected effectiveness of treatments can be an important milestone on the road of personal genomics. Investigating the different responds to treatments can sometimes lead to the discovery of a combination of genetic variants which can be utilized to predict with great certainty the effectiveness of the specific treatment or drug on a new patient. Achievement of this goal can be influenced by numerous factors: the a prior knowledge of the effect of treatment, the nature of effect and the factors concerning it, the sampling protocol, the size of biobank and the type and quality of information assigned to the samples, examining the appropriate genomic regions, the type of instruments used for genomic measurements, the quality of information provided by these instruments and the type of statistical methods used for evaluating the data. While precise biological interpretation of the different responds to the specific treatment is very difficult especially in case of multifactorial diseases, to discover statistically efficient biomarkers can be a realistic goal in most cases. Our team's main aim is to find the factors influencing the discovery of biomarkers used for treatment selection and to find or develop the bioinformatics tools and medical biologic methodology that can be efficiently used for biomarker discovery. We aim to develop general methodology and protocols but we mainly focus on diseases already examined by DGCI and DMIS (e.g. asthma, acute lymphoblastic leukemia).
The bioinformatics methods developed by our team are based on the Bayesian statistical framework. It offers a normative way for knowledge representation and for learning from observations. Concerning utility theory the Bayesian framework can be used to make optimal decisions. It establishes an important connection between statistics and knowledge engineering because it is capable to incorporate heterogeneous a prior knowledge into the statistical learning process. Besides these, Bayesian framework provides a computational framework for the learning and using of complex probabilistic models because it enables the using of various stochastic simulation methods. This finally results in the appearance of computation-intensive statistics.
Bayesian Multilevel Analysis (levels: bivariate, multivariate, interaction, causal domain model) is a new, promising general method, which can be very useful in case of datasets with small sample sizes and multiple testing problems. Bayesian methods are effectively used in the field of genetic association studies (GAS). In the Bayesian framework, Bayesian belief networks (which are computationally intensive) have many advantages: (i) discovery of direct associations, (ii) multivariate management of missing variables, (iii) the ability to incorporate various types of a prior knowledge and (iv) discovery of causal effects and relationships.
The bioinformatics project is granted by the NKTH, in which we participate as a member of the Genagrid Consortium (http://www.genagrid.com/).
Collaborations:
Running grants
NKFIH-K112872; Csaba Szalai, Genetic and immunological investigations of pathomechanism in asthma and allergy; 53 888 000 Ft; 2015-2019.
NKFIH, Grant No. K115861, D.J. Erdélyi-Extracellular vesicle studies in paediatric malignant haematology, 31 788 000 Ft, 2015-2019.
STIA-KF-17; Szalai Csaba, Hosszú nem-kódoló RNS-ek vizsgálata asztmában és COPD-ben; 4 155 705 Ft; 2017.
NKFIH PD109200, Semsei ÁF,Pharmacogenetic study of anthracycline therapy in childhood acute lymphoblastic leukemia, 24 795 000 Ft, 2014-2016.
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Dr. Csaba Szalai, University Professor |
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Dr. Judit Cs. Sági, PhD Student
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Dr. Ágnes F. Semsei, Assistant lecturer |
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Zsófia Gál, PhD Student |
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Dr. András Gézsi, Research Fellow |
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Mónika S. Vángor, Assistant |
2020
2019
2018
2017
2016
2015
2014
2013
2012
2011
2010
2009
2008
2007
2006
2005
2004
2003
2002
2001
2020
ESHAL, 2nd How to Diagnose and Treat: Acute Leukaemia
online, June 30 - July 02, 2020
25th EHA Annual Congress
online, June 11-21, 2020
2019
10th International Conference on Immunology & Immunogenetics
London, UK, 30-31 October 2019
SIOP 2019
Lyon, France, October 23 – 26, 2019
XVIII. “Genetikai Műhelyek Magyarországon” konferencia
Szeged, Hungary, 13 September 2019
SOHO 2019
Houston, Texas, US, September 11–14, 2019
Magyar Hematológiai és Transzfuziológiai Társaság XXVII. Kongresszusa
Pécs, Hungary, 23-25 May 2019
Semmelweis Egyetem, PhD Tudományos Napok
Budapest, Hungary, 25-26 April 2019
2018
Magyar Humángenetikai Társaság XII. Kongresszusa
Debrecen, Hungary 06-08 September 2018
CLLS, 11th Biennial Childhood Leukemia and Lymphoma Symposium
Helsinki, Finland, May 21-22 2018.
Semmelweis Egyetem, Orvos-, Fogorvos- és Gyógyszerésztudományi Diákköri Konferencia
Budapest, Hungary, 7-9 February 2018
2017
1st Childhood Leukemia Early Adverse Reactions Conference 2017
Elsinor, Denmark, 1-3 June 2017
XXXIII. Országos Tudományos Diákköri Konferencia, Orvos- és Egészségtudományi szekció
Pécs, Hungary, 18-21 April 2017
PhD Scientific Days 2017
Budapest, Hungary, 11–12 April 2017
XI. Szent-Györgyi Albert Konferencia
Budapest, Hungary, April 2017
XXII. Bolyai Konferencia
Budapest, Hungary, 18-19 March 2017
Acute Leukemia XVI.
Munich, Germany, 19-22 February 2017
Semmelweis Egyetem, Orvos-, Fogorvos- és Gyógyszerésztudományi Diákköri Konferencia
Budapest, Hungary, 8-10 February 2017
2016
Onco Update
Budapest, Hungary, 25-26 November 2016
Semmelweis Symposium
Budapest, Hungary, 17-18 November 2016
Magyar Humángenetikai Társaság XI. Kongresszusa és Méhes Károly Genetikai Továbbképző Napok
Pécs, Hungary, 12-15 October 2016
A Magyar Személyre Szabott Medicina Társaság VII. kongresszusa
Herceghalom, Hungary, 26-27 August 2016
YSA PhD Symposium
Vienna, Austria, 9-10th June 2016
10th Biennial Childhood Leukemia Symposium
Athens, Greece, 25-26 April 2016
Semmelweis Egyetem PhD Napok
Budapest, Hungary, 7-8 April 2016
Semmelweis Egyetem, Orvos-, Fogorvos- és Gyógyszerésztudományi Diákköri Konferencia
Budapest, Hungary, 10-12 February 2016
2015
Semmelweis Symposium
Budapest, Hungary, 5-6th November 2015
European Society of Pharmacogenomics and Personalised Therapy Third Conference
Budapest, Hungary, 7-9 October 2015
Magyar Hematológiai és Transzfúziológiai Társaság XXV. Kongresszusa
Budapest, Hungary, 14-16 May 2015
Semmelweis Egyetem PhD Tudományos Napok
Budapest, Hungary, 9-10 April 2015
XX. Korányi Frigyes Tudományos Fórum
Budapest, Hungary, 12-13 March 2015
Semmelweis Egyetem Orvos-, Fogorvos- és Gyógyszerésztudományi Diákköri Konferencia
Budapest, Hungary, 11-13 February 2015
Semmelweis International Students’ Conference 2015
Budapest, Hungary, 11-12 February 2015
2014
Biológus Tudományos Diákköri Konferencia
Budapest, Hungary, 22 November 2014
I. Astellas Ifjú Kutatói Szimpózium
Pécs, Hungary, 24 September 2014
Magyar Humángenetikai Társaság X. Jubileumi Kongresszusa
Budapest, Hungary, 4-6 September 2014
A Magyar Allergológiai és Klinikai Immunológiai Társaság 41. Kongresszusa
Balatonalmádi, Hungary, 9-11 May 2014
Semmelweis Egyetem PhD Tudományos Napok
Budapest, Hungary, 10-11 April 2014
Semmelweis Egyetem, Orvos-, Fogorvos- és Gyógyszerésztudományi Diákköri Konferencia
Budapest, Hungary, 2-4 April 2014
2013
Semmelweis Symposium 2013. Molecular mechanisms and therapeutic targets in inflammatory diseases
Semmelweis University, Budapest, Hungary, 7-9 November 2013
2nd Conference of European Society of Pharmacogenomics and Theranostics (ESPT) "Pharmacogenomics: From Cell to Clinic"
Lisbon, Portugal, 26-28 September 2013
ERS Annual Congress
Barcelona, Spain, 7-11 September 2013
Amerikai Magyar Orvosszövetség (HMAA) nyári konferenciája
Balatonfüred, Hungary, 16-17 August 2013
9th Young Scientist Association (YSA) PhD Symposium
Vienna, Austria, 19-20 June 2013
Magyar Allergológiai és Klinikai Immunológiai Társaság 41. Kongresszusa
Balatonalmádi, Hungary, 9-11 May 2013
Semmelweis Egyetem, PhD Tudományos napok
Budapest, Hungary, 11-12 April 2013
2011
Magyar Személyre Szabott Medicina Társaság II. éves Kongresszusa
Eger, Hungary, 23-24 September 2011
2010
Magyar Humángenetikai Társaság VIII. kongresszusa
Debrecen, Hungary, 2-4 September 2010
A Magyar Laboratóriumi Diagnosztikai Társaság 55. Nagygyűlése
Pécs, Hungary, 26-28 August 2010
Magyar Biokémiai Egyesület 2010. évi Vándorgyűlése
Semmelweis Egyetem Elméleti Orvostudományi Központja, Budapest, Hungary, 25-28 August 2010
CSCDA 2010
Leuven, Belgium, 25-27 August 2010
EACR-21, the 21st Meeting of the Association for Cancer Research
Oslo, Norway, 26-29 June 2010
Orsolya Csorba, Ágnes F.Semsei, Dániel Erdélyi, Eszter Barabás, Mónika S.Vángor, Géza Schermann, Éva Hadadi, Viktor Virág,, András Falus, Csaba Szalai, Examination of GST and CCR5 gene polymorphisms in children with acute lymphoid leukemia in Hungarian population
6. PhD-Symposium, Medical University of Vienna
Vienna, Austria, 16-17 June 2010
12th International Paediatric Haematology and Oncology Update Meeting
Edinborough, UK, 29-30 April 2010
Semmelweis University PhD Scientific Days 2010
Budapest, Hungary, 15-16 April 2010
3rd HUNGARIAN-SINGAPOREAN WORKSHOP on SYSTEMS BIOLOGY and COMMUNICATION SYSTEMS
Budapest, Hungary, 29-30 March 2010
Late Effects in Cancer Survivors
Sheffield, UK, 3-4 March 2010
2009
Sarasota splash: Update in Biomedical and Clinical Sciences The Helmsley Sandcastle Hotel Sarasota, Lido Beach Florida 41st Annual Scientific Meeting of HMAA
Sarasota, Florida, US, 25-30 October 2009
2nd Central European Congress on Obesity
Budapest, Hungary, 1-3 October 2009
ECCO15-ESMO34 Congress
Berlin, Germany, 20-24 September 2009
PHARMACOGENOMICS & PERSONALIZED MEDICINE
Hinxton, UK, 12-15 September 2009
Genetikai Műhelyek Magyarországon
Szeged, Hungary, 11 September 2009
Machine Learning in System Biology 2009 (MLSB09)
Ljubljana, Slovenia, 5-6 September 2009
Allergy & Asthma Symposium: Bridging Innate and Adaptive Immunity
Bruges, Belgium, 28-29 May 2009
Human Genome Variation Society, Human Variome Project, Towards Establishing Standards
Vienna, Austria, 22 May 2009
MTA 2009. évi közgyűléséhez kapcsolódó tudományos előadás
Budapest, Hungary, 6 May 2009
Semmelweis University PhD Scientific Days 2009
Budapest, Hungary, 30-31 March 2009