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Im Bereich der Forschung erhalten Sie zum einen eine Übersicht über die einzelnen Arbeitsgruppen (ausgehend von den jeweiligen Arbeitsgruppenleitern).
Die Forschungsgruppen von Fr. Dr. Behnaz Pezeshkpoor, Fr. Dr. Kathrin Czogalla-Nitsche und Frau Dr. Heike Singer finden Sie unter der AG Prof. Dr. J. Oldenburg.
 

AG Prof. Dr. J. Oldenburg

Der Forschungsschwerpunkt unserer Arbeitsgruppe liegt bei den Enzymen des Vitamin K Zyklus (VKORC1 und GGCX) und den Vitamin K abhängigen Proteinen. Neben diesen bildet die Untersuchung heriditärer Störungen des Gerinnungssystems, insbesondere Defekte im Faktor VIII und IX (Hämophilie A und B), im Faktor XIII sowie im VWF die Grundlage weiterer wichtiger Projekte.
Unsere Forschungsaktivitäten werden durch Förderung seitens des BMBF (Nationales Genom Forschungs-Netzwerk- Cardiovaskuläre Erkrankungen), der DFG, der Universitätsklinik Bonn (BONFOR Programm) und der Industrie unterstützt.

  • Vitamin K cycle
  • F VIII immunogenicityPhenotype-Genotype Correlation in blood coagulation disordersFaktor-XIII-GenetiGenotype-phenotype correlation in von Willebrand disease

The role of vitamin K beyond coagulation
Vitamin K is essential to drive a post-translational modification, called γ-carboxylation, of 15 different vitamin K dependent proteins including several clotting factors but also non-haemostatic proteins such as GRP, MGP, Osteocalcin, PRGP1 and 2, TMG3 and 4 and Gas6. These vitamin K dependent non-haemostatic proteins have function in calcification, cell-signalling and other not yet identified pathways.

Our Emmy Noether research group study the function of the vitamin K cycle beyond blood coagulation and the interplay of the enzymes VKORC1, VKORC1-like1, and GGCX with vitamin K dependent proteins in cellular and mice models under heathy and disease conditions.

Group members:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   Dr. rer. nat. Katrin Czogalla-Nitsche, PhD
Emmy-Noether group leader / Principle investigator
Room: 2G/302
Phone: +49 (0)228-287 16783
Email: Enable JavaScript to view protected content.

Prof. Dr. med. Johannes Oldenburg
Email: Enable JavaScript to view protected content.

Suvoshree Ghosh
PhD student
Email: Enable JavaScript to view protected content.

Francesco Forin
PhD student
Email: Enable JavaScript to view protected content.

Anna-Lena Buhl
PhD student
Email: Enable JavaScript to view protected content.

Katrin Kraus
Technician (BTA)
Email: Enable JavaScript to view protected content.

Heike Höfer
Technican (BTA)
Email: Enable JavaScript to view protected content.

Publications:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          Czogalla KJ, Liphardt K, Höning K, Hornung V, Biswas A, Watzka M, Oldenburg J.; VKORC1 and VKORC1L1 have distinctly different oral anticoagulant dose-response characteristics and binding sites.; Blood Adv. 2018 Mar;27;2(6):691-702.
Czogalla KJ, Biswas A, Höning K, Hornung V, Liphardt K, Watzka M, Oldenburg J.; Warfarin and vitamin K compete for binding to Phe55 in human VKOR.; Nat Struct Mol Biol. 2017 Jan;24(1):77-85.
Czogalla KJ, Biswas A, Rost S, Watzka M, Oldenburg J.; The Arg98Trp mutation in human VKORC1 causing VKCFD2 disrupts a di-Arginine-based ER retention motif.; Blood. 2014 Aug 21;124(8):1354-62
Czogalla KJ, Biswas A, Wendeln AC, Westhofen P, Müller CR, Watzka M, Oldenburg J.; Human VKORC1 mutations cause variable degrees of 4-hydroxycoumarin resistance and affect putative warfarin binding interfaces.; Blood. 2013 Oct 10;122(15):2743-50.  

Stand: 04. September 2020

Dr. Heike Singer (Junior Research Group Leader)

Staff:
Payal Chawla (PhD student on EDUC8 ITN)
Melanie Rath (Technical assistant)

Research area: FVIII immunogenicity

In about 20-30% of patients with severe Haemophilia A (HA), treatment with replacement FVIII is complicated due to the development of inhibitory antibodies against the substituted concentrates. The mutation type and position in the protein plays a pivotal role in the risk of inhibitor development. It is believed that F8 nonsense null mutations provoke higher immunogenicity against replacement FVIII by lacking self-FVIII protein that could be presented to the immune system. However, surprisingly, non- sense mutations located in the light chain (A3C1C2 domains; last 1/3 of the protein), have higher risk to develop inhibitors when compared to nonsense mutations located in the heavy chain (A1A2B do- mains; first 2/3 part of protein). Accordingly, the highest inhibitor risk (70 %) appears, for two pre-terminal stop codons (PTCs) located in the A3 domain. This is against expectation as the protein should be largely available to get presented and recognized as self-protein. Molecular mechanism to explain this phenomenon is still lacking, however it was suggested that a rapid degradation due to the stop mutation could be responsible. To study the most native fate of FVIII mRNA and protein our group is generating induced pluripotent stem cells (iPSCs) from HA-patients.
                 
Differentiation of IPS cells into vascular endothelial cells offers us a patient-specific cellular model to study intracellular fate of F8 mRNA and protein. Preliminary data of IPS differentiated vECs from HA-patients with different null mutations confirmed the existence of intracellular FVIII protein even if truncated. Therefor our major aim in our ongoing research is to identify the exact trafficking route of such truncated proteins (secretory or degradative pathway) and to find out if peptides from endogenous FVIII variants are presented by MHC-I and MHC-II on the surface of vascular endothelial cells. If so, we expect mutation-specific changes in the collection of MHC-presented peptides, that might have an effect on the inhibitor development associated with the specific mutation of a patient.

Funding:
BHAP2017: EARLY CAREER INVESTIGATOR AWARD (Bayer)
GLEA2018: Günther Landbeck Excellence Award
EDUC8: Early Stage Researchers EDUCational Program on Factor VIII Immunogenicity. (Marie Skłodowska-Curie Actions (MSCA) Innovative Training Networks (ITN) H2020-MSCA-ITN-2019)

Publications:
1) Jamil M.*, Singer H.*, Al-Rifai R., Nüsgen N., Rath M., Strauss S., Andreou I., Oldenburg J., El-Maarri O. Molecular analysis of fetal and adult primary human liver sinusoidal endothelial cells: a comparison to other endothelial cells. Int. J. Mol. Sci 2020 (PEER REVIEW)                                                                                 2) Pezeshkpoor B, Gazorpak M, Berkemeier AC, Singer H, Pavlova A, Biswas A, Oldenburg J. In silico and in vitro evaluation of the impact of mutations in non-severe haemophilia A patients on assay discrepancies. Ann Hematol. 2019 Aug;98(8):1855-1865. doi: 10.1007/s00277-019-03691-1. Epub 2019 Apr 17.
3) Singer H, Biswas A, Zimmer N, Messaed C, Oldenburg J, Slim R, El-Maarri O. NLRP7 inter- domain interactions: the NACHT-associated domain is the physical mediator for oligomeric assembly. Mol Hum Reprod. 2014 Oct;20(10):990-1001.
5) Singer H, Walier M, Nüsgen N, Meesters C, Schreiner F, Woelfle J, Fimmers R, Wienker T, Kalscheuer VM, Becker T, Schwaab R, Oldenburg J, El-Maarri O. Methylation of L1Hs promoters is lower on the inactive X, has a tendency of being higher on autosomes in smaller genomes and shows inter-individual variability at some loci. Hum Mol Genet. 2012 Jan 1;21(1):219-35.
5) Singer H, Nüsgen N, El-Maarri O. SIRPH: an HPLC-based SNuPE for quantitative methylation measurement at specific CpG sites. Methods Mol Biol. 2011;791:89-100.
6) El-Maarri O, Walier M, Behne F, van Üüm J, Singer H, Diaz-Lacava A, Nüsgen N, Niemann B, Watzka M, Reinsberg J, van der Ven H, Wienker T, Stoffel-Wagner B, Schwaab R, Oldenburg J. Methylation at global LINE-1 repeats in human blood are affected by gender but not by age or natural hormone cycles. PLoS One. 2011 Jan 19;6(1):e16252.
7) El-Maarri O, Singer H, Klein C, Watzka M, Herbiniaux U, Brackmann HH, Schröder J, Graw J, Müller CR, Schramm W, Schwaab R, Haaf T, Hanfland P, Oldenburg J. Lack of F8 mRNA: a novel mechanism leading to hemophilia A. Blood. 2006 Apr 1;107(7):2759-65.

Stand: 12.10.2020

In the department of molecular haemostaseology 25 genes involved in blood coagulation are routinely investigated. The scientific interests of the group are focused on genotype-phenotype correlation in patients with rare blood coagulation disorders. Haemophilia, a deficiency of coagulation factor VIII and IX is of special interest. Different genetic defects have been identified and functionally studied. New insights in the genetic alteration as deep intronic changes leading to haemophilia are thoroughly explored. An interesting issue addressed in our group is the association F8 missense mutations and their impact on the FVIII activity, especially in the context of discrepancy between one stage clotting and chromogenic assays. Inhibitor development, is of special interest and different genetic factors as mutation type, polymorphisms in the immune-response genes and HLA are currently investigated. Another scientific area focuses on factor 5 gene. New mutations, leading to APC resistance have been identified and structurally and functionally studied.
The group is involved in a number of national and international studies including ABIRISK, analyzing the mechanisms and consequences of immunization against biopharmaceutical products and OBSITI aiming to evaluate patient and therapy related variables on immune tolerance induction course.

Working group:
Priv.-Doz. Dr. Anna Pavlova, MD, PhD
Dr. Behnaz Pezeshkpoor, PhD
Dr. Thilo Albert, PhD

Selection of publications:
1. Goodeve AC, Pavlova A, Oldenburg J. Genomics of bleeding disorders. Haemophilia. 2014 May;20 Suppl 4:50-3.
2. Pavlova A, Delev D, Pezeshkpoor B, Müller J, Oldenburg J. Haemophilia A mutations in patients with non-severe phenotype associated with a discrepancy between one-stage and chromogenic factor VIII activity assays. Thromb Haemost.2014 May 5;111(5):851-61.
3. Pahl S, Pavlova A, Driesen J, Oldenburg J. Effect of F8 B domain gene variants on synthesis, secretion, activity and stability of factor VIII protein. Thromb Haemost. 2014 Jan;111(1):58-66.
4. Pezeshkpoor B, Pavlova A, Oldenburg J, El-Maarri O. F8 genetic analysis strategies when standard approaches fail. Hamostaseologie. 2014;34(2):167-73.
5. Pavlova A, Oldenburg J. Defining severity of hemophilia: more than factor levels. Semin Thromb Hemost. 2013 Oct;39(7):702-10. doi: 10.1055/s-0033-1354426. Epub 2013 Sep 11. Review.
6. Pavlova A. F8 gene and phenotype: single player in a team? Blood. 2013 May,9;121(19):3784-5.
7. Pahl S, Pavlova A, Driesen J, Müller J, Pötzsch B, Oldenburg J. In vitro characterization of recombinant factor VIII concentrates reveals significant differences in protein content, activity and thrombin activation profile.Haemophilia. 2013 May;19(3):392-8.
8. Schwaab R, Pavlova A, Albert T, Caspers M, Oldenburg J. Significance of F8 missense mutations with respect to inhibitor formation. Thromb Haemost. 2013 Mar;109(3):464-70. doi: 10.1160/TH12-07-0521. Epub 2013 Jan 10. PubMed PMID: 23306409
9. Caspers M, Pavlova A, Driesen J, Harbrecht U, Klamroth R, Kadar J, Fischer R,Kemkes-Matthes B, Oldenburg J. Deficiencies of antithrombin, protein C andprotein S - practical experience in genetic analysis of a large patient cohort.Thromb Haemost. 2012 Aug;108(2):247-57.
10. Luxembourg B, Delev D, Geisen C, Spannagl M, Krause M, Miesbach W, Heller C, Bergmann F, Schmeink U, Grossmann R, Lindhoff-Last E, Seifried E, Oldenburg J,Pavlova A. Molecular basis of antithrombin deficiency. Thromb Haemost. 2011Apr;105(4):635-46.
11. Pavlova A, Delev D, Lacroix-Desmazes S, Schwaab R, Mende M, Fimmers R, Astermark J, Oldenburg J. Impact of polymorphisms of the major histocompatibility complex class II, interleukin-10, tumor necrosis factor-alpha and cytotoxic T-lymphocyte antigen-4 genes on inhibitor development in severe hemophilia A. J Thromb Haemost. 2009 Dec;7(12):2006-2015. doi: 10.1111/j.1538-7836.2009.03636.x. PubMed PMID: 19817985.

Stand: 02. Dezember 2014

Plasma Factor XIII is a protransglutaminase circulating as a heterotetramer composed of two catalytic A and two protective B subunits. It functions by crosslinking preformed fibrin clots and also by crosslinking fibrinolytic inhibitors like alpha 2-antiplasmin to the fibrin clot making the clot mechanically and chemically stronger and resistant to premature fibrinolysis. Deficiency of this protein can result in a bleeding predisposition commonly known as Factor XIII deficiency. Factor XIII deficiency can be inherited or acquired. The inherited form is of two types: A) a rare severe form (1 in 1 to 4 million prevalence and B) a more frequent mild heterozygous form. The inherited form of this deficiency is characterized by mutations occurring in the F13A1 and F13B genes; the genes for the A and B subunits respectively.
The Factor XIII group works on two aspects: A) The genotypic and phenotypic diagnosis of patients suffering from severe and mild Factor XIII deficiency and B) The structure-functional aspects of Factor XIII. The Factor XIII group has in the past characterized and reported a large number of Factor XIII deficiency patients with mutations in F13A and F13B genes. The efforts of the Factor XIII group in the last few years have brought the otherwise lesser known mild Factor XIII deficiency into focus. This group also is one of the few groups in the world that is involved in determining the molecular etiology of heterozygous mutations reported from mild Factor XIII deficiency patients. Current efforts include expressing these mutations in heterologous systems and evaluating the in vitro expression phenotype in a multitude of assays each phenotypically representing a unique aspect of Factor XIII. Current efforts are also directed towards solving the Factor XIII A2B2 heterotetramer structure and eventually characterizing it in terms of complex dynamics.

Working group:
Dr. (biol.) Arijit Biswas, Scientist
Priv.-Doz. Dr. (med.) Vytautas Ivaskevicius, Clinician
Ms. Sneha Gupta, Ph.D student

Recent publications from this group are:

Biswas A, Ivaskevicius V, Thomas A, Varvenne M, Brand B, Rott H, Haussels I, Ruehl H, Scholz U, Klamroth R, Oldenburg J. Eight novel F13A1 gene missense mutations in patients with mild FXIII deficiency: in silico analysis suggests changes in FXIII-A subunit structure/function. Ann Hematol. 2014 Jun 3.

Souri M, Biswas A, Misawa M, Omura H, Ichinose A. Severe congenital Factor XIII deficiency caused by novel W187X and G273V mutations in the F13A gene; diagnosis and classification according to the ISTH/SSC guidelines. Haemophilia. 2014 Mar;20(2):255-62.

Biswas A, Ivaskevicius V, Thomas A, Oldenburg J. Coagulation factor XIII deficiency. Diagnosis, prevalence and management of inherited and acquired forms. Hamostaseologie. 2014;34(2):160-6.

Biswas A, Thomas A, Bevans CG, Ivaskevicius V, Oldenburg J. In vitro secretion deficits are common among human coagulation factor XIII subunit B missense mutants: Correlations with patient phenotypes and molecular models. Hum Mutat. 2013 Aug 2.

Ivaskevicius V, Biswas A, Thomas A, Lyonga S, Rott H, Halimeh S, Kappert G, Klammroth R, Scholz U, Eberl W, Harbrecht U, Gnida C, Hertfelder HJ, Marquardt N, Oldenburg J. A common F13A1 intron 1 variant IVS1+12(A) is associated with mild FXIII deficiency in Caucasian population. Ann Hematol. 2013 Jul;92(7):975-9.

Biswas A, Ivaskevicius V, Seitz R, Thomas A, Oldenburg J. An update of the mutation profile of Factor 13 A and B genes. Blood Rev. 2011 Sep;25(5):193-204.

Ivaskevicius V, Biswas A, Bevans C, Schroeder V, Kohler H.P, Rott H, Halimeh S, Petrides P.E, Lenk H, Krause M, Miterski B, Harbrecht U, Oldenburg J. Identification of eight novel coagulation Factor XIII subunit A mutations: Implied consequences for structure and function. Haematologica. 2010 Feb 23.

Ivaskevicius V, Biswas A, Loreth R, Schroeder V, Ohlenforst S, Rott H, Krause M, Kohler H.P, Scharrer I, Oldenburg J. Mutations affecting disulphide bonds contribute to a fairly common prevalence of F13B gene defects: Results of a genetic study in 14 families with Factor XIII B deficiency. Haemophilia. 2010 Jul 1; 16(4):675-82.


Stand: 02. Dezember 2014

Von Willebrand disease (VWD) project is focused on understanding of the molecular basis of different types of VWD to establish phenotype-genotype correlations.
In VWD project, we explore genotype and phenotype characteristics of a cohort of patients with VWD with the aim of dissecting the distribution of mutations in different types of VWD and correlate them to the clinical disease severity. In addition, our project intends to elucidate the pathophysiological mechanisms of detected novel missense and potential splice mutations by in vitro gene expression studies in mammalian cell lines and in vivo transcript analysis respectively. Moreover, possible structural impact of the mutations on VWF protein is studied by in silico homology modeling. Additionally, we plan to study behavior of the recombinant wilde-type and mutant VWF strings in vitro under shear-stress conditions resembling the blood flow in vessels using an automated shear-controlling device.

Working group:
Dr. Hamideh Yadegari, PhD

Publications:

Yadegari H, Driesen J, Pavlova A, Biswas A, Ivaskevicius V, Klamroth R, Oldenburg J. Insights into pathological mechanisms of missense mutations in C-terminal domains of von Willebrand factor causing qualitative or quantitative von Willebrand disease. Haematologica. 2013 Aug;98(8):1315-23. doi: 10.3324/haematol.2013.084111. Epub 2013 Mar 28. PubMed PMID: 23539537; PubMed Central PMCID: PMC3729914.

Yadegari H, Driesen J, Pavlova A, Biswas A, Hertfelder HJ, Oldenburg J. Mutation distribution in the von Willebrand factor gene related to the different von Willebrand disease (VWD) types in a cohort of VWD patients. Thromb Haemost. 2012 Oct;108(4):662-71. Epub 2012 Aug 7. PubMed PMID: 22871923.

Yadegari H, Driesen J, Hass M, Budde U, Pavlova A, Oldenburg J. Large deletions identified in patients with von Willebrand disease using multiple ligation-dependent probe amplification. J Thromb Haemost. 2011 May;9(5):1083-6. doi: 10.1111/j.1538-7836.2011.04260.x. PubMed PMID: 21410641.


Stand: 02. Dezember 2014


Forschungsgruppe PD Dr. B. Pezeshkpoor


Staff:
Ann-Cristin Berkemeier Rath (Technical assistant/WHK)
Nadja Sereda (Master student)


Research Areas:

Approximately 30% of patients with hemophilia A develop inhibitory antibodies to coagulation factor VIII. Antibody formation is both the most serious and the most expensive complication of hemophilia. At our institute, these antibodies are readily detected using the Bethesda assay and an ELISA, so that a determination can be made as to whether the patient is positive and what the titer is. In the Lumitope project, the aim is to determine the antibody specificity, i.e. against which exact part (epitopes) of FVIII an antibody is directed. This provides information about the frequency of different antibodies against specific epitopes, as well as the possibility of developing a therapy.

Platelet biogenesis is a complex process that relies on the expression and functionality of a number of genes. To date, many different genes have been described to play a role in the synthesis and maturation of megacryocytes into functional platelets. Nevertheless, the cause of the disruption of functionality or the reduction in the number of platelets in half of all congenital cases with thrombocytopenia (reduction in the number of platelets) or thrombocytopathy (disruption of platelet functionality) cannot be elucidated. After the generation of induced pluripotent stem cells (iPS) from the blood of patients with thrombocytopenia, they are differentiated into megakaryocytes to study platelet biogenesis.

We are always on the lookout for potential PhD students and Masters Students intending to do their Master’s thesis. Enquiry regarding current available positions can be sent to Dr. Behnaz Pezeshkpoor: Enable JavaScript to view protected content..

Link to the publications of the group: https://pubmed.ncbi.nlm.nih.gov/?term=behnaz+Pezeshkpoor


Selected Publications

1. Preisler B*, Pezeshkpoor B*, Banchev A, Fischer R, Zieger B, Scholz U, Rühl H, Kemkes-Matthes B, Schmitt U, Redlich A, Unal S, Laws HJ, Olivieri M, Oldenburg J, Pavlova A. Familial Multiple Coagulation Factor Deficiencies (FMCFDs) in a Large Cohort of Patients-A Single-Center Experience in Genetic Diagnosis. J Clin Med. 2021 Jan 18;10(2):347. doi: 10.3390/jcm10020347.
2. Jankowska KI, McGill J, Pezeshkpoor B, Oldenburg J, Atreya CD, Sauna ZE. Clinical manifestation of hemophilia A in the absence of mutations in the F8 gene that encodes FVIII: role of microRNAs. Transfusion. 2020 Feb;60(2):401-413. doi: 10.1111/trf.15605. Epub 2019 Nov 29. PMID: 31785023.
3. B. Pezeshkpoor, M. Gazorpak,A-C. Berkemeier, Singer H., Pavlova A., Biswas A. and J. Oldenburg In-silico and in-vitro evaluation of the impact of mutations in non-severe haemophilia A patients on assays discrepancies. Ann Hematol (2019). https://doi.org/10.1007/s00277-019-03691-1
4. Pezeshkpoor B, Czogalla KJ, Caspers M, Berkemeier AC, Liphardt K, Ghosh S, Kellner M, Ulrich S, Pavlova A, Oldenburg J. Variants in FIX propeptide associated with  Vitamin K antagonist hypersensitivity: functional analysis and additional data confirming the common founder mutations. Ann Hematol. 2018 Jun;97(6):1061-1069.
5. Pezeshkpoor B, Schreck U, Biswas A, Driesen J, Berkemeier AC, Pavlova A, Müller J, Oldenburg J. An in silico and in vitro approach to elucidate the impact of residues flanking the cleavage scissile bonds of FVIII. PLoS One. 2017 Jul 6;12(7):e0180456.
6. Pezeshkpoor B, Castoldi E, Mahler A, Hanel D, Müller J, Hamedani NS, Biswas A, Oldenburg J, Pavlova A. Identification and functional characterization of a novel F5 mutation (Ala512Val, FVBonn ) associated with activated protein C resistance. J Thromb Haemost. 2016 Jul;14(7):1353-63.
7. Pezeshkpoor B, Berkemeier AC, Czogalla KJ, Oldenburg J, El-Maarri O. Evidence of pathogenicity of a mutation in 3' untranslated region causing mild haemophilia A. Haemophilia. 2016 Jul;22(4):598-603.
8. Pezeshkpoor B, Theophilus BD, Guilliatt AM, Oldenburg J, Williams MD, El-Maarri O. Novel characterization of a breakpoint in F8: an individualized approach to gene analysis when PCR and MLPA results contradict. Haemophilia. 2015 May;21(3):392-7.
9. Pezeshkpoor B, Zimmer N, Marquardt N, Nanda I, Haaf T, Budde U, Oldenburg J,  El-Maarri O. Deep intronic 'mutations' cause hemophilia A: application of next generation sequencing in patients without detectable mutation in F8 cDNA. J Thromb Haemost. 2013 Sep;11(9):1679-87.
10. Pezeshkpoor B, Rost S, Oldenburg J, El-Maarri O. Identification of a third rearrangement at Xq28 that causes severe hemophilia A as a result of homologous recombination between inverted repeats. J Thromb Haemost. 2012 Aug;10(8):1600-8.  
11. Pezeshkpoor B, Oldenburg J. F8 gene: embedded in a region of genomic instability representing a hotspot of complex rearrangements. Haemophilia. 2015 Jul;21(4):513-5.
12. Pezeshkpoor B, Pavlova A, Oldenburg J, El-Maarri O. F8 genetic analysis strategies when standard approaches fail. Hamostaseologie. 2014;34(2):167-73.


AG PD Dr. O. El Maarri

Arbeitsgruppe El-Maarri: Gene regulation

The group has the focus on factor VIII: from basic biology to therapies. Factor VIII is an essential coagulation factor whose deficiency leads to hemophilia A. This factor is part of the tenase complex that lead to the activation of factor X and thus to a normal clot formation. The symptoms in hemophilia A patients are treated by introducing the missing factor VIII (or a functional alternative) to the blood circulation. Although this is an effective strategy but it will not provide a therapy. Recently gene therapy using AAV vectors became realistic approach to treat hemophilia A patients, however some complications would prohibit good amount of patients from benefiting from such long term therapeutical benefit. Thus, we are interested in investigating alternative approach based on cellular therapies; toward this direction we are following basic investigations on the synthesis of factor VIII in native cells in the human body.

  • Intracellular route(s) of factor VIII secretion and degradation
  • Role of Autophagy in secretions of coagulation factors
  • Characterization of endothelial cells Liver Sinusoidal cells (LSECs)
  • Derivation of LSECs using defined factors

    In addition the groups has general interest in the following fields:
  • Epigenetics in health and disease (like human aneuploidies).
  • Line 1 methylation in health and disease.
  • Bioinformatics analysis of epi/genomic biological data.

Nicole Nüsgen, MTA

Ashraf  El-Taher, Bioinformatics Master student

Rawya Al-Rifai, PhD student

Salima Hazouri, PhD student

Muhammad Ahmar Jamil, PhD student

Priv. Doz. Dr. Osman El-Maarri (group leader)


Current Guests:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               Mira Ibrahim, Master student
Doha Chrayteh, Master student

Selected publications:

1. Amit Sharma, Muhammad Ahmer Jamil, Nicole Nuesgen, Albertas Dauksa, Antanas Gulbinas, Wolfgang A. Schulz, Johannes Oldenburg, Osman El-Maarri. Detailed methylation map of LINE-1 5´ promoter region reveals hypomethylated CpG hotspots associated with tumor tissue specificity. Mol. Gen. Genom. Med. 2019 May;7(5):e601

2. Muhammad A. Jamil, Amit Sharma, Nicole Nuesgen, Behnaz Pezeshkpoor, Andre Heimbach, Anna Pavlova, Johannes Oldenburg and Osman A. El-Maarri. F8 inversions at Xq28 causing hemophilia A are associated with specific methylation changes: Implication for molecular epigenetic diagnosis. Front. Genet. - Epigenomics and Epigenetics. 2019 May 29;10:508.

3. Muhammad A. Jamil, Heike Singer, Rawya Al-Rifai, Nicole Nüsgen, Melanie Rath, Sascha Strauss, Ioanna Andreou, Johannes Oldenburg, and Osman El-Maarri. Molecular analysis of fetal and adult primary human liver sinusoidal endothelial cells: a comparison to other endothelial cells. In press.

Stand: 12.11.2020


AG PD Dr. Arijit Biswas

The Biochemistry and Chemiinformatic group

The focus of our group is on characterizing the genetic/structural/functional aspects of coagulation proteins using an array of biochemical and computational approaches. Our main protein of interest is the Coagulation Factor XIII (FXIII), which is a plasma circulating pro-transglutaminase complex responsible for covalent crosslinking of the pre-formed soluble fibrin clot converting it to a insoluble one resistant to premature fibrinolysis. Inherited deficiency of Factor XIII (FXIII) is a rare coagulation disorder which results in severe bleeding diathesis. The severe form of FXIII deficiency is caused by homozygous or compound heterozygous mutations in FXIII genes. Investigations from our group have suggested the existence of a mild form of FXIII deficiency as well resulting exclusively from heterozygous genetic variants. Furthermore, using a clustered approach involving in-silico modelling complemented by biochemical analyses, our group has shed light on the activation mode of FXIII, roles of Calcium binding to FXIII, regulatory importance of the FXIIIB subunit and its genetic variability amongst other things. Our group recently used an integrative hybrid approach to build the first full-atom structural model for the plasma FXIII complex. Apart from FXIII, we collaborate with multiple other groups in structure functional investigations of other coagulation proteins like vWF, Factor VIII and VKORC1. We also are involved in generating inhibitors that will work in pro-coagulant scenarios in close collaboration with Prof. Diana Imhof from Pharmaceutical Institute in University of Bonn.

Our research activities are supported by funding received from DFG, international research bodies like WFH and from industry based competitive grants provided to PD Dr. Arijit Biswas and Prof. Oldenburg (Shire, CSL-Behring, Novo Nordisk, Bayer and Biotest to name a few).

We are always on the lookout for potential PhD students and Masters Students intending to do their Master’s thesis. Enquiry regarding current available positions can be sent at: Enable JavaScript to view protected content. 

Lab website: www.arijitbiswaslab.com

PD Dr. rer. nat. Arijit Biswas
Group leader
Room: 2G/308
Phone: +49 (0)228-287 19428
Email: Enable JavaScript to view protected content.

Dr. rer. nat. Sneha Singh
Post-doctoral fellow
Email: Enable JavaScript to view protected content.  

Mr. Haroon Javed
PhD student
Email: Enable JavaScript to view protected content.

Ms. Samhitha Urs Ramaraje Urs
PhD student
Email: Enable JavaScript to view protected content.

Mr. Sibaram Sadrangi
Master student
Email: Enable JavaScript to view protected content.    


Previous members of the group:

Dr rer. nat. Anne Thomas
Presently working as clinical research associate at IQVIA, Germany
Dr. (biol.) Mohammad Suhail Akhter
Presently Asst. Prof. at Jazan University, Jazan, Saudi Arabia
Ms. Sophie Lyonga
Presently MTA at Zotzklimas, Düsseldorf, Germany
Dr. Nadia Mir-Montazeri
Presently medical intern at Universitäre Psychiatrische Dienste Bern
Isabelle Claus
Medical intern

1. Hopp MT, Alhanafi N, Paul George AA, Hamedani NS, Biswas A, Oldenburg J, Pötzsch B, Imhof D. Molecular Insights and Functional Consequences of the Interaction of Heme with Activated Protein C. Antioxid Redox Signal. 2020 Aug 20.
2. Bäuml CA, Paul George AA, Schmitz T, Sommerfeld P, Pietsch M, Podsiadlowski L, Steinmetzer T, Biswas A, Imhof D. Distinct 3-disulfide-bonded isomers of tridegin differentially inhibit coagulation factor XIIIa: The influence of structural stability on bioactivity. Eur J Med Chem. 2020 Sep 1;201:112474.
3. Bhakuni T, Sharma A, Biswas A, Bano S, Mahapatra M, Saxena R, Jairajpuri MA. Identification and characterization of a novel variant in C-terminal region of Antithrombin (Ala427Thr) associated with type II AT deficiency leading to polymer formation. J Thromb Thrombolysis. 2020 Oct;50(3):678-685.
4. Singh S, Nazabal A, Kaniyappan S, Pellequer JL, Wolberg AS, Imhof D, Oldenburg J, Biswas A. The Plasma Factor XIII Heterotetrameric Complex Structure: Unexpected Unequal Pairing within a Symmetric Complex. Biomolecules. 2019 Nov 21;9(12):765.
5. Sharma A, Biswas A, Liu H, Sen S, Paruchuri A, Katsonis P, Lichtarge O, Chand Dakal T, Maulik U, Gromiha MM, Bandyopadhyay S, Ludwig M, Holz FG, Loeffler KU, Herwig-Carl MC. Mutational Landscape of the BAP1 Locus Reveals an Intrinsic Control to Regulate the miRNA Network and the Binding of Protein Complexes in Uveal Melanoma. Cancers (Basel). 2019 Oct 19;11(10):1600.
6. Singh S, Dodt J, Volkers P, Hethershaw E, Philippou H, Ivaskevicius V, Imhof D, Oldenburg J, Biswas A. Structure functional insights into calcium binding during the activation of coagulation factor XIII A. Sci Rep. 2019 Aug 5;9(1):11324.
7. Singh S, Akhter MS, Dodt J, Volkers P, Reuter A, Reinhart C, Krettler C, Oldenburg J, Biswas A. Identification of Potential Novel Interacting Partners for Coagulation Factor XIII B (FXIII-B) Subunit, a Protein Associated with a Rare Bleeding Disorder. Int J Mol Sci. 2019 May 31;20(11):2682.
8. Singh S, Akhter MS, Dodt J, Sharma A, Kaniyappan S, Yadegari H, Ivaskevicius V, Oldenburg J, Biswas A. Disruption of Structural Disulfides of Coagulation FXIII-B Subunit; Functional Implications for a Rare Bleeding Disorder. Int J Mol Sci. 2019 Apr 22;20(8):1956.
9. Akhter MS, Singh S, Yadegari H, Ivaskevicius V, Oldenburg J, Biswas A. Exploring the structural similarity yet functional distinction between coagulation factor XIII-B and complement factor H sushi domains. J Thromb Thrombolysis. 2019 Jul;48(1):95-102.
10. Ahmed S, Yadegari H, Naz A, Biswas A, Budde U, Saqlain N, Amanat S, Tariq S, Raziq F, Masood S, Pavlova A, Shamsi TS, Oldenburg J. Characterization of the mutation spectrum in a Pakistani cohort of type 3 von Willebrand disease. Haemophilia. 2019 Nov;25(6):1035-1044.
11. Bäuml CA, Schmitz T, Paul George AA, Sudarsanam M, Hardes K, Steinmetzer T, Holle LA, Wolberg AS, Pötzsch B, Oldenburg J, Biswas A, Imhof D. Coagulation Factor XIIIa Inhibitor Tridegin: On the Role of Disulfide Bonds for Folding, Stability, and Function. J Med Chem. 2019 Apr 11;62(7):3513-3523.
12. Melzer C, Sharma A, Peters S, Aretz S, Biswas A, Holz FG, Loeffler KU, Herwig-Carl MC. Basal cell carcinomas developing independently from BAP1-tumor predisposition syndrome in a patient with bilateral uveal melanoma: Diagnostic challenges to identify patients with BAP1-TPDS. Genes Chromosomes Cancer. 2019 Jun;58(6):357-364.

Complete list of publications of PD Dr. rer. nat. Arijit Biswas can be found at:
https://www.ncbi.nlm.nih.gov/myncbi/1XMrxSbZr4vAi/bibliography/public/

Stand: 15.02.2021


Portal für den wissenschaftlichen Nachwuchs der Universität Bonn


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Lehre

Studium und Lehre

Das Institut für Experimentelle Hämatologie und Transfusionsmedizin bietet Lehrveranstaltungen für Studierende der Humanmedizin, der Zahnmedizin, der Pharmazie und im Rahmen des Masterstudiengangs Medical Immunosciences and Infection an. Lehrverantwortlicher des Instituts ist PD Dr. H. Rühl, erreichbar über das Sekretariat unter +49 228 287-15176.

Diese Praktika behandelt die wesentlichen Themen des Fachgebietes, die für eine Tätigkeit am Patientenbett relevant sind:

  • Herstellung von Blutprodukten
  • Blutgruppensysteme und immunhämatologische Labordiagnostik
  • Methodische Grundlagen und prätransfusionelle Verträglichkeitsdiagnostik
  • Immunhämatologische Labordiagnostik
  • Praktische Durchführung einer Bluttransfusion
  • Klinik, Diagnostik und Therapie hämorrhagischer und thrombophiler Diathesen

Die Inhalte des Praktikums werden in einer begleitenden Hauptvorlesung vertieft. Seit dem Sommersemester 2020 stehen die Lehrinhalte auch zum Selbststudium in eCampus zur Verfügung, das Praktikum wird als Seminar im Inverted-classroom-Format durchgeführt.

Neben der Hauptvorlesung wird für besonders interessierte Studierende die Vorlesung Hämotherapie als fakultative Ergänzungsveranstaltung angeboten:

  • Physiologie und Pathophysiologie der Hämatopoiese und des Hämostasesystem            
  • Maternale Inkompatibilitäten und autoimmunhämolytische Anämien
  • Auto- und Alloimmunthrombozytopenien (NAIT, FAIT, ITP, TTP, HUS)
  • Indikationsstellung der Gabe von Hämotherapeutika, Zelltherapeutika und Transfusion
  • Klinik, Diagnostik und Therapie hämorrhagischer oder thrombophiler Diathesen
  • Therapie mit gerinnungsaktiven Hämotherapeutika
  • Grundlagen des HLA-Systems Bedeutung für Stammzelltransplantationen

Die PJ-Ausbildung im Fach Transfusionsmedizin ist in das Wahltertial Interdisziplinäre Onkologie integriert. Die Lernziele und die zu absolvierenden Leistungen sind in einem Lernziel- sowie einem Leistungskatalog definiert.
Die Ausbildung erfolgt zwei Wochen im Blutspendedienst, im Blutdepot, im immunhämatologischen und hämostaseologischen Labor sowie den Ambulanzen unseres Instituts (Allgemeine Gerinnungsambulanz, Hämophiliezentrum, Zelltherapie). Die Tätigkeiten im Blutspende- und Zelltherapiebereich bestehen vorwiegend in der Teilnahme an der ärztlichen Betreuung der Vollblut- und Thrombozytenspende, aber auch in der Behandlung autologer und allogener Stammzellspender. Im Blutdepot und im immunhämatologischen Labor ist die Mitarbeit bei Blutgruppenbestimmungen, Antikörperdifferenzierungen, Abklärungen von immunhämolytischen Anämien und weiterer immunhämatologischer Diagnostik Teil der Ausbildung. Darüber hinaus sollten die PJ-Studierenden die wesentlichen Grundlagen der klinischen Anwendung von Blutkomponenten kennenlernen, insbesondere die jeweiligen Indikationen, Kontraindikationen und das Notfallmanagement. In unserer Gerinnungsambulanz und im Hämophiliezentrum nehmen die Studierenden an der Behandlung von Patienten mit angeborenen und erworbenen thrombophilen und hämorrhagischen Diathesen teil.

Für Studierende der Humanmedizin im zweiten Studienabschnitt bieten wir ein einwöchiges (42 Zeitstunden) Blockpraktikum als Wahlfach an.

Wissenschaftliche Arbeiten (Promotionsarbeiten für Mediziner und Naturwissenschaftler) sind insbesondere im Bereich der Hämostaseologie möglich. Interessierte Studenten können sich gerne jederzeit bewerben.

Notruf 112

Ärztlicher Notdienst 116 117

Giftnotrufzentrale
Tel: +49 228 19240

Notfallzentrum Bonn

Kindernotfallzentum Bonn

UKB-Telefonzentrale
+49 228 287 0

Information gemäß § 6 Medizinprodukte-Betreiberverordnung "Beauftragter für Medizinproduktesicherheit"

Sehr geehrte Damen und Herren,

gemäß § 6 Medizinprodukte-Betreiberverordnung steht Ihnen das Universitätsklinikum Bonn im Zusammenhang mit Meldungen über Risiken von Medizinprodukten, Informationen zu Rückrufen oder Warn- und Sicherheitshinweisen sowie bei der Umsetzung von notwendigen korrektiven Maßnahmen unter folgender E-Mailadresse zur Verfügung: Enable JavaScript to view protected content.

Diese E-Mailadresse richtet sich vorzugsweise an Kontaktpersonen von Behörden, Herstellern und Vertreibern von Medizinprodukten.

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