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Department of Cellular and Molecular Pathology

Current project:

Implementation of a complex genome profiling diagnostic algorithm for patients with congenital and developmental abnormalities (CONGEN)

INTRACELLULAR SIGNALING IN GASTRIC AND ESOPHAGEAL ADEN OCARCINOMA
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FINDING AND VALIDATING MOLECULAR TARGETS IN GASTRIC TUMOR STEM CELLS FOR DEVELOPMENT OF NOVEL ANTI-CANCER THERAPEUTIC STRATEGIES

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Previous projects:

 

DIFFERENT POLYMORPHISMS IN CYTOKINES GENETIC PROFILE INVOLVED IN VIRAL INFECTIONS AND GRAFT REJECTION IN TRANSPLANT RECIPIENTS
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NEW MECHANISMS OF DISEASE IN MALIGNANT MYELOPROLIFERATIVE DISORDER – A COMPLEX APPROACH FROM GENE AND MOLECULE TO CELL PATHOLOGY
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NEW STRATEGIES OF CELL THERAPY USING UMBILICAL CORD BLOOD HEMATOPOIETIC PROGENITOR CELLS
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THERAPUTICAL POTENTIAL OF HEMATOPOIETIC STEM CELLS IN LIVER DISEASE
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TISSUE ENGINEERING TECHNIQUES WITH APPLICATIONS IN SURGICAL TREATMENT OF INTESTINAL FISTULA
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INTEGRATED RESEARCH NETWORK FOR THE STUDY OF MICROBIAL BIOFILMS DEVELOPED ON CELLULAR SUBSTRATA AND PROSTETIC DEVICES TO IMPROVE THE DIAGNOSIS AND TREATMENT OF BIOFILM ASSOCIATED INFECTIONS
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PROMOTION WITHIN AN EUROPEAN AND INTERNATIONAL PARTNERSHIP OF BIOMEDICAL RESEARCH UNDER EXTREME LIFE CONDITIONS
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PROMOTION OF ROMANIAN PSYCHIATRIC GENETICS RESEARCH THROUGH INTERNATIONAL PARTNERSHIP IN GENETIC AND EPIGENTIC STUDIES OF BIPOLAR DISORDER
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Different polymorphisms in cytokines genetic profile involved in viral infections and graft rejection in transplant recipients

ACRONYM: SNP-CK - CEEX-M1-148/2006

CO – STEFAN S. NICOLAU INSTITUTE OF VIROLOGY, BUCHAREST (principal investigator: Carmen C. Diaconu, scientific responsible: Irina Alexiu)
P1 - FUNDENI CLINICAL INSTITUTE, BUCHAREST: THE LIVER TRANSPLANTATION CLINIC AND THE KIDNEY TRANSPLANTATION CLINIC
P2 - RESEARCH BASE FOR MULTIPLE USERS ON MOLECULAR BIOLOGY FROM UNIVERSITY OF BUCHAREST.
P3 - VIROLOGY AND IMMUNOLOGY DIVISION FROM “VICTOR BABES” HOSPITAL OF INFECTIOUS AND TROPICAL DISEASES, BUCHAREST
P4 - SIGNAL TRANSDUCTION UNIT FROM LUDWIG INSTITUTE FOR CANCER RESEARCH, BRUSSELS, BELGIUM

 Summary. Research tendencies in transplant biology field, presently, point to immunologic evaluation, rapid andaccurate virological diagnostic, and the response to immunosuppression. Transplant studies around the world, are focused on a deeper understanding of the genetic mechanisms involved in facilitating or tempering graft rejection or post-transplant viral infections, as well as on molecular mechanisms, which sustains certain immunosuppressive therapy response particularities. In this context, the objectives of the project were to:

 

A wide range of investigations have been performed for detection, diagnosis and monitoring viral infections and graft rejection in liver and renal transplant recipients. The results of the proposed study help to elucidate the role of the cytokine genes in the complex gene network involved in immune response, and especially in organ transplant immunity. Investigating for the first time Romanian patients’ imunogenetic profiles, enable us to hypothesise on genetic risk factors involved in transplantation.

Our results were published and/or presented at different national and international confernces and/or are to be published in international journals.
C.A. Bucsa, B. D. Tacu, C. Dobrea, E. Kerezsy, I. Ursuleac, I. Alexiu, V. Uscatescu, I. Sinescu, Severe aplastic anemia in renal transplant recipients caused by chronic parvovirus B19 infection, XXIInd International Congress of Transplantation Society, 10-14 august 2008 Sydney, Australia.
Irina Alexiu, Catalina Luca, Camelia Grancea, Andreea Toana,Gratiela Tardei, Camelia Sultana, Bogdan Dorobantu, Simona Dima, Irinel Popescu, Marieta Costache, Mihai Stoian, Carmen C. Diaconu, IL-6 and TNFa phenotypes associations – possible risk factors for HBV, HCV or CMV reccurence in liver transplant recipients, 2nd Mediterranean Clinical Immunology Meeting Antalya 2008,4-7 octombrie.
Gratiela Tardei, Alexiu I. Bleotu C., Grancea C., Tacu D., Hrehoret D., Sinescu I., Popescu I., Diaconu, C. C., Masurarea comparativa a citokinelor prin metodele CBA (cytometric bead array) şi ELISA, Al 4-lea Congres Naţional de Citometrie, Predeal 2008 7-10 mai.
Irina Alexiu, Catalina Luca, Bogdan Dorobantu, Andreea Toana,Denisa Dragu, Roxana Dragusel, Dragos Romanescu, Gratiela Tardei, Doina Hrehoret, Simona Dima, Irinel Popescu, Marieta Costach, Carmen C. Diaconu, Posibile implicaÅ£ii ale SNP-urilor prezente în genele IL-6 ÅŸi TNFa în frecvenÅ£a episoadelor de rejet acut la primitorii de transplant hepatic,, Conferinta Societatea NaÅ£ionala de Imunologie 2008 – Busteni, 24-26 septembrie
Irina Alexiu, Catalina Luca, Bogdan Dorobantu, Andreea Toana,Denisa Dragu, Roxana Dragusel, Dragos Romanescu, Gratiela Tardei, Doina Hrehoret, Simona Dima, Irinel Popescu, Marieta Costache, Carmen C. Diaconu, Posibile implicaÅ£ii ale SNP-urilor prezente în genele IL-6 ÅŸi TNFalfa în frecvenÅ£a episoadelor de rejet acut la primitorii de transplant hepatic, Simpozionul “Medicina TransplaÅ£ională” –Institutul Clinic Fundeni ÅŸi Institutul de Boli Cardiovasculare "Prof. Dr. C. C. Iliescu", 27 - 28 noiembrie 2008, BucureÅŸti,
Irina Alexiu, Catalina Luca, Dragos Romanescu, Andreea Toana,Denisa Dragu, Roxana Dragusel, Bogdan Dorobantu, Gratiela Tardei, Doina Hrehoret, Simona Dima, Irinel Popescu, Marieta Costache, Mihai Stoian, Carmen C. Diaconu, Posibile implicaÅ£ii ale asocierilor de diferite fenotipuri ale IL-6 ÅŸi TNFa în frecvenÅ£a episoadelor de rejet acut la primitorii de transplant hepatic,Conferinta Viasan (Modulul 1) 2008 – Sinaia, 28-30 septembrie.
G Tardei, I Alexiu, CC Diaconu, S Dima, D Ticu, I Sinescu, I Popescu, Citokine proinflamatorii prin metoda Cytometric Bead Array, Sesiunea ştiinţifica Spitalul Victor Babes, octombrie 2008.
Grigoroiu-Serbanescu M, Herms S, Mühleisen TW, Georgi A, Diaconu CC, Strohmaier J, Czerski P, Hauser J, Leszczynska-Rodziewicz A, Jamra RA, Babadjanova G, Tiganov A, Krasnov V, Kapiletti S, Neagu AI, Vollmer J, Breuer R, Rietschel M, Nöthen MM, Cichon S, Propping P., Variation in P2RX7 candidate gene (rs2230912) is not associated with bipolar I disorder and unipolar major depression in four European samples. Am J Med Genet B Neuropsychiatr Genet. Mar 27 [Epub ahead of print] (2009).
Staerk J, Kallin A, Royer Y, Diaconu CC, Dusa A, Demoulin JB, Vainchenker W, Constantinescu SN , JAK2, the JAK2 V617F mutant and cytokine receptors. Pathol Biol (Paris). Elsevier, 55(2):88-91, 2007, ISI – Nominalizat la premiile Amedeus 2008.
C.N. Zaharia, Andrei Mihai Popovici, Irina Alexiu, A Transplant Web Application for Viral Infection and Genetic Data The 3rd International Conference Euro-Mediterranean medical Informatics and Telemedicine (EMMIT 2007), Mangalia, 2007.

 

 

 

NEW MECHANISMS OF DISEASE IN MALIGNANT MYELOPROLIFERATIVE DISORDER – A COMPLEX APPROACH FROM GENE AND MOLECULE TO CELL PATHOLOGY

ACRONYM: SMPC
CEEX-M1-111/2006

CO - NATIONAL INSTITUTE FOR RESEARCH AND DEVELOPMENT IN PATHOLOGY AND BIOMEDICAL SCIENCES, BUCHAREST
P1 - CAROL DAVILA UNIVERSITY OF MEDICINE AND PHARMACY, BUCHAREST
P 2 – COLTEA CLINICAL HOSPITAL, BUCHAREST
P3 – STEFAN S. NICOLAU INSTITUTE OF VIROLOGY, BUCHAREST (principal investigator: Dr. Carmen C. Diaconu; scientific responsible: Dr. Mihaela Chivu)
P4 - SIGNAL TRANSDUCTION UNIT FROM LUDWIG INSTITUTE FOR CANCER RESEARCH, BRUSSELS, BELGIUM

Summary. Chronic myeloproliferative disorders (CMPDs) are a heterogeneous group of hematologic malignancies arising from a multipotent hematopoietic stem cell. The molecular pathogenesis of these disorders has been poorly understood, except for chronic myeloid leukemia (CML). Cytogenetic and molecular studies of CMPDs identified chromosomal translocations that generate fusion genes involving tyrosine kinases, and thus advanced the elucidation of pathogenic mechanisms of BCR/ABL negative CMPDs.
The recently identified unique activating mutation in JAK2 kinase that activates the downstream signaling pathways appears to be the key genetic event for most of CMPDs patients.

In this context JAK2 became an attractive candidate gene for PV, ET, and/or IMF pathogenesis.

In this proposal we will concentrate on the molecular diagnosis of the JAK2 V617F in BCR-ABL negative MPDs in our collection at the Victor Babes Institute and we will establish the procedures for detection of this mutation in patients treated at the Hematology Departments of the Coltea Hospital and of other Hematology Departments in Romania. Several procedures will be employed, namely allele specific PCR, restriction-PCR, sequencing and quantitative TaqMan PCR, which allows the diagnosis of heterozygous versus holmozygous status. Cells from JAK2 V617F positive and negative MPD patients will be examined for blood cell differentiation in colony assays, response to cytokines and for the JAK2 V617F-negative cells will be examined for additional genetic abnormalities.
Patients negative for JAK2 V617F will be investigated for other genetic abnormalities using molecular genetic methods and modern cytogenetic tests (FISH with locus-specific, centromere-specific and chromosome-specific probes).

Samples from MPD patients in dynamics will be invaluable for further identification of which genetic or epigenetic events may promote evolution of Polycythemia Vera or Thrombocythemia versus Myelofibrosis and eventually to acute myeloid leukemia.

The accomplishment of this project would prove essential for implementation of advanced methods of molecular diagnosis in Romania that will allow the integration of our research teams in The Frame Programs Of European Union. The institutions involved, „Victor Babes” National Research-Development Institute, „Carol Davila” University of Medicine and Pharmacy, Clinic of Hematology, Coltea Hospital and „Stefan S. Nicolau” Institute of Virology, form an excellent team that may advance the molecular and cellular investigation in myeloproliferative diseases.

NEW STRATEGIES OF CELL THERAPY USING UMBILICAL CORD BLOOD HEMATOPOIETIC PROGENITOR CELLS

ACRONYM: CORDCELL - CEEX-M1-85/2006

CO - FILANTROPIA CLINICAL HOSPITAL, BUCHAREST (cord blood collection)
P1 - FUNDENI CLINICAL INSTITUTE, BUCHAREST (stem cell banking facility, pediatric transplant)
P2 – STEFAN S. NICOLAU INSTITUTE OF VIROLOGY, BUCHAREST (infectious agents detection, hematopoietic stem cell isolation and culture; animal model experiments); principal investigator: Mihaela Chivu.
P3 – NATIONAL INSTITUTE FOR RESEARCH AND DEVELOPMENT IN PATHOLOGY AND BIOMEDICAL SCIENCES, BUCHAREST (animal model experiments, imunohistochemistry)
P4 – INSTITUTE OF ONCOLOGY, BUCHAREST (irradiation, animal model experiments).

Summary. The interest regarding hematopoietic stem cells increased in last decade due to their potential to supply essential material for advanced therapies like gene therapy, cellular therapy and tissue regeneration. Hematopoietic stem cell promise for clinical therapy is nevertheless restricted due to reduced availability of traditional stem cell sources: bone marrow and peripheral blood. The umbilical cord blood is used in special in pediatric cases, but his application is rapidly extending to adult patients. It is considered an excellent stem cell source especially for patients who have un rare HLA constellation and need an urgent transplant procedure.

The project specific aim is to find effective methods for improving clinical results of using umbilical cord blood stem cells in transplant, by obtaining an optimum cell graft. For that purpose, the establishment of effective methodology, technically relevant, for ex vivo cultivation of these cells, will be done, through manipulation of culture microenvironment by cytokines supplementation.
Animal studies will be realized in order to investigate the efficiency of allotransplant clinical protocols using umbilical cord blood stem cells, for initiate cell therapy procedures in patients with malignant disorders, hepatic failure and inborn congenital disorders. The project will conduct to organization of a bank facility for umbilical cord blood according with international quality standards and ethical rules.

Due to this study’s objectives that conduct to setting up new techniques and procedures for treatment of very severe diseases, the project perfectly integrates in the regeneration medicine field, covering several thematic areas likeInnovative therapeutic approaches and intervention, and Translational research in major diseases.

THERAPUTICAL POTENTIAL OF HEMATOPOIETIC STEM CELLS IN LIVER DISEASE

ACRONYM: LIVERSTEM - CEEX-M1-65/2006

CO - FUNDENI CLINICAL INSTITUTE, BUCHAREST (apheresis procedure, liver surgery, human stem cell transplant)
P1 – INSTITUTE OF ONCOLOGY, BUCHAREST (irradiation, animal model experiments)
P2 – NATIONAL INSTITUTE FOR RESEARCH AND DEVELOPMENT IN PATHOLOGY AND BIOMEDICAL SCIENCES, BUCHAREST (animal model experiments, immunohistochemistry)
P3 - STEFAN S. NICOLAU INSTITUTE OF VIROLOGY, BUCHAREST (hematopoietic stem cell culture); principal investigator: Mihaela Chivu.

Summary. As the disparity between patients waiting for liver transplantation and available organs grows, there are increasing efforts to find potentially viable alternatives, such as adult living donor liver transplantation, use of marginal donors (older donors, diabetics, steatotic grafts), use of ABO incompatible or non-heart-beating donor, but also transplantation of mature hepatocytes or of stem/progenitor cells and potential of transplanting xenogeneic organs and cells. Cellular therapy in liver disease represents a new, promising therapeutically approach. The adult stem cells from mobilized peripheral blood may represent a considerable advantage in their use for the therapy of hepatic lesions because could be harvested from live donors by a minimally invasive technique.

The project’s specific aim is in vivo assessment of hematopoietic stem cells and in vitro derived hepatic cells capacity to participate in liver regeneration. The specific activities are: differentiation of hematopoietic stem cells through hepatic-cell-like suitable to participate in liver regeneration after transplant; development of the animal model with hepatic failure for in vivo assessment of liver regeneration capacity of adult stem cells; implementation of cellular therapy procedure for patients with end stage liver disease.

The proposed research has the potential to increase the data about liver stem cell biology, representing a new source of data for the future clinical trials.

TISSUE ENGINEERING TECHNIQUES WITH APPLICATIONS IN SURGICAL TREATMENT OF INTESTINAL FISTULA

ACRONYM: INGITIS - CEEX-M1-139/2006

CO - FUNDENI CLINICAL INSTITUTE, BUCHAREST (animal model experiments)
P1 – STEFAN S. NICOLAU INSTITUTE OF VIROLOGY, BUCHAREST (mesenchymal stem cell isolation and culture); principal investigator: Mihaela Chivu
P2 – NATIONAL INSTITUTE FOR RESEARCH AND DEVELOPMENT IN BIOLOGICAL SCIENCES, BUCHAREST (collagen matrix synthesis)
P3 – AGRONOMY AND VETERINARY MEDICINE UNIVERSITY, BUCHAREST (animal model experiments)

Summary. The project involves complex research activities realized in partnership by 5 highly specialized units in complementary top domains. Through the tissue engineering methods proposed for intestinal fistula treatment, the project follows to perform some innovative techniques, which involves original pre-testing experiments on animal models.

The project’s aim is the development of a new 3D sandwich matrix for intestinal fistula surgical treatment. The matrix includes the culture of autologous mesenchymal stem cell on 3D collagen structure and arterial wall. The biological product will be characterized (histological) and tested (biochemical, bacteriological). The obtained 3D matrix will be experimental tested on animals. If favorable results will be obtained on animal models, the possibility for treating also human voluntaries patients will be considered.

INTEGRATED RESEARCH NETWORK FOR THE STUDY OF MICROBIAL BIOFILMS DEVELOPED ON CELLULAR SUBSTRATA AND PROSTETIC DEVICES TO IMPROVE THE DIAGNOSIS AND TREATMENT OF BIOFILM ASSOCIATED INFECTIONS

ACRONYM: BIOFILM - CEEX-M1-142/2006

CO – UNIVERSITY OF BUCHAREST, ROMANIA
P1 – STEFAN S. NICOLAU INSTITUTE OF VIROLOGY, BUCHAREST
(principal investigator : Coralia Bleotu)
P2 – CAROL DAVILA UNIVERSITY OF MEDICINE AND PHARMACY, BUCURESTI
P3 – POLITECHNIC UNIVERSITY, BUCURESTI
P4 – NATIONAL INSTITUTE FOR RESEARCH AND DEVELOPMENT IN BIOLOGICAL SCIENCES, BUCHAREST
P5 – INSTITUTE FOR THE MOTHER AND CHILD PROTECTION, BUCHAREST
P6 – PROF. C.C. ILIESCU INSTITUTE FOR CARDIOVASCULAR DISEASES, BUCHAREST

Summary. Biofilms are involved in 60 to 85% of infections that occur in developed countries, characterized by slow onset, middle intensity symptoms, chronic evolution and resistance to antibiotic treatment. Taking into account the differences in physiology and susceptibility to antibiotics of biofilm embedded bacteria, the international concerted efforts for finding new methods for the study of microbial adherence and aggregation, as well as new strategies for the diagnosis and therapy of biofilm associated infections are absolutely needed. The magnitude of the problem is highlighted by the decision taken at the level of the European Society for Clinical Microbiology and Infectious Diseases (ESCMID) to fund, starting with 2005, the ESCMID Biofilm Study Group (ESGB).

The main objective of the project is to promote and disseminate the methodological and scientific information on biofilms and their medical relevance, in the purpose to improve the results of prevention, diagnosis and therapy of biofilm associated infections. Specific activities: the setting up of the biological material background required for the optimal development of the scientific activities (collection of microbial strains isolated from medical biofilms, the investigation of intrinsic and extrinsic parameters of microbial adherence on cellular substrata and prosthetic devices by using original experimental models for the development of artificial monospecific biofilms; the in vitro assessment of the phenotypic resistance of adhered and biofilm embedded microbial strains to different antimicrobial factors; pilot study for the implementation in clinical laboratory of an optimized method for susceptibility testing and assessment of therapeutic doses for biofilm associated infections; elaboration of guidelines for prevention, diagnosis and therapy of infections with microorganisms adhered to tissues and prosthetic devices. This project is framed in the thematic area No. 1 (Health) and No. 11 (Basic sciences) following the acquisition of advanced knowledge in a fundamental research field with large scale practical application in the public health domain, by prediction of opportunity and efficiency of biofilm associated infections therapy, and by approaching the microbial resistance.

PROMOTION WITHIN AN EUROPEAN AND INTERNATIONAL PARTNERSHIP OF BIOMEDICAL RESEARCH UNDER EXTREME LIFE CONDITIONS

ACRONYM: PPEICBCEV - CEEX-M3-C3 134/2006

CO - STEFAN S. NICOLAU INSTITUTE OF VIROLOGY, BUCHARESTI, (principal investigator : Toparceanu Florica)
P1 - CAROL DAVILA UNIVERSITY OF MEDICINE AND PHARMACY, BUCURESTI
P2 - Romanian Polar Research Institute

Summary. The purpose of this project is to establish a Consortium in view of participating with projects in European programs such as FP 7, Europolar ERA-NET, and international ones: InternaÅ£ional Polar Year 2007-2009, cooperations within the Antarctic Treaty, in order to enhance the international visibility of the Romanian scientific research activities developed in Romania and in the Antarctic „Law-Racoviţă” Station, by means of:

The innovative, multinational and multidisciplinary Health Surveillance System in the Polar Area (HSSP), to the development of which we shall contribute by ours proposed actions will improve the generation standardization, acquirement and analysis of the biomedical data regarding polar zones. It will also stimulate the experimental progress in the field of biomedical research by multiple applications in the humanitarian, military, space voyages spheres, in the natural and industrial disasters, as well as of other environmental challenges.

The international project which will be developed during the period October 2006 – April 2009 for the purpose of implementation of this system in which we shall participate, is complex research project, as it includes studies of immunology, physiology, epidemiology, public health, professional health, social and behavioral sciences and photo/chronobiology, leading to a better efficient prevention and treatment of any adverse effect of the extreme life and work conditions in man’s health.

The international and multidisciplinary collaboration promoted by our proposed actions in the field of the taxonomy and physiology of viruses as well as of the biomedical applications of the Antarctic organisms, will assure the acquirement of an advanced knowledge in the basic science Biology for the next FP7 protocols.

Promotion of Romanian psychiatric genetics research through international partnership in genetic and epigentic studies of bipolar disorder

ACRONYM: BPGEN

Summary. The project is intended to take advantage of a longlasting collaboration of the project director with outstanding german scientists in the field of psychiatric genetics. The first objective of the project is the extention of the Romanian involvement in international psychiatric genetics projects through adding the biological molecular dimension to the clinical-biometric cooperation and the setting up of a Romanian psychiatric genetics research group capable to participate in international collaborative projects.

The second objective of the project is the informational and technological transfer through the training of Romanian researchers in genetic techniques (genome scan, secventiation, identification of new genes) and epigenetics [the microarray techniques DMH (differential methylation hybridization); MSPCR (Methylation Specific PCR)] in Germany. The practical use of these methods will occur in a pilot study intended to replicate some candidate genes for bipolar (manic-depressive) disorder (particularly G72 gene) and to explore their methylation pattern in a Romanian patient sample partially recruited during the current project.

The above mentioned objectives will be achieved through the collaboration among a research unit based in the biggest psychiatric hospital of Romania (SCPDAO-GENPSI), an institute of the Romanian Academy (IVN) and three institutes of the University of Bonn (Germany) [Institute of Medical Genetics (C1), Institute of Human Genetics (C2), Institute of Neuropathology (C3)] and the Central Institute of Mental Health of Mannheim, Germany (C4). The project considers short research stays of the Romanian researchers in Germany, visits of the German scientists to Romania for short courses, practical training and participation in joint conferences and the effective performance of an exploratory pilot study using Romanian clinical and biological material for testing new psychiatric genetic hypotheses (putative involvement of altered methylation patterns of genes associated with bipolar disorder). Moreover, the collection of DNA from a Romanian sample of bipolar patients and normal controls is intended; this sample will be integrated in a large European sample for genetic study of bipolar disorder and will serve to replicating genes identified in other European samples.

The project is compatible with the thematic area „Health”, first of all with the thematic field 1.2.2. by concerning the genetic ethiology of a major chronic psychiatric disorder and with the thematic field 1.2.1. because the project is also intended to collect DNA from a representative Romanian sample of bipolar patients and normal controls to be integrated in a large European sample for genetic study of bipolar disorder. Likewise, the project is compatible with the thematic field 1.1.2. since it will apply non-invasive methods (DNA methylation and genome scan methods) in an exploratoy study to detect putative epigenetic and genetic causes of bipolar disorder and to develop the competence of the Romanian researchers in using these techniques.

 

Previous projects:

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