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Romania
Citizenship:
Ph.D. degree award:
Mihai
Ciubotaru
Senior Research Scientist first Degree CS I
-
INSTITUTUL NATIONAL DE CERCETARE - DEZVOLTARE PENTRU FIZICA SI INGINERIE NUCLEARA " HORIA HULUBEI " - IFIN - HH
Researcher | Teaching staff | Scientific reviewer
>20
years
Personal public profile link.
Expertise & keywords
V(D)J Recombination
Transposons
Recombinant DNA
fluorescence spectroscopy
Immunology
Molecular biology
Lymphomas
Molecular biology
Projects
Publications & Patents
Entrepreneurship
Reviewer section
The development in oncology of novel radiopharmaceuticals and nuclear techniques for diagnostic imaging and personalized treatment at molecular level PN-III-P1-1.2-PCCDI-2017-0769
Call name:
PN-III-P1-1.2-PCCDI-2017-0769
2018
-
2020
Role in this project:
Project coordinator
Coordinating institution:
INSTITUTUL NATIONAL DE CERCETARE - DEZVOLTARE PENTRU FIZICA SI INGINERIE NUCLEARA " HORIA HULUBEI " - IFIN - HH
Project partners:
INSTITUTUL NATIONAL DE CERCETARE - DEZVOLTARE PENTRU FIZICA SI INGINERIE NUCLEARA " HORIA HULUBEI " - IFIN - HH (RO)
Affiliation:
INSTITUTUL NATIONAL DE CERCETARE - DEZVOLTARE PENTRU FIZICA SI INGINERIE NUCLEARA " HORIA HULUBEI " - IFIN - HH (RO)
Project website:
Abstract:
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Electromagnetic shielding structures for biological safety in PW laser-target interaction systems
Call name:
ELI-RO 17
2016
-
2019
Role in this project:
Partner team leader
Coordinating institution:
INSTITUTUL NATIONAL DE CERCETARE DEZVOLTARE PENTRU FIZICA LASERILOR, PLASMEI SI RADIATIEI - INFLPR RA
Project partners:
INSTITUTUL NATIONAL DE CERCETARE DEZVOLTARE PENTRU FIZICA LASERILOR, PLASMEI SI RADIATIEI - INFLPR RA (RO); INSTITUTUL NATIONAL DE CERCETARE - DEZVOLTARE PENTRU FIZICA SI INGINERIE NUCLEARA " HORIA HULUBEI " - IFIN - HH (RO)
Affiliation:
INSTITUTUL NATIONAL DE CERCETARE DEZVOLTARE PENTRU FIZICA LASERILOR, PLASMEI SI RADIATIEI - INFLPR RA (RO)
Project website:
Abstract:
Investigations of laser-matter generated Electromagnetic pulses over living cells and shielding structures for biological protection.
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Design and testing of a new family of specific drug HIV Integrase inhibitors which do not interfere with V(D)J recombination
Call name:
Joint Applied Research Projects - PCCA 2013 - call
PN-II-PT-PCCA-2013-4-0930
2014
-
2017
Role in this project:
Coordinating institution:
SPITALUL CLINIC "COLENTINA" BUCURESTI
Project partners:
SPITALUL CLINIC "COLENTINA" BUCURESTI (RO); APEL LASER S.R.L. (RO); INSTITUTUL DE BIOCHIMIE (RO); INSTITUTUL NATIONAL DE CERCETARE - DEZVOLTARE PENTRU FIZICA SI INGINERIE NUCLEARA " HORIA HULUBEI " - IFIN - HH (RO)
Affiliation:
SPITALUL CLINIC "COLENTINA" BUCURESTI (RO)
Project website:
http://www.apellaser.com/hivinvdj/
Abstract:
After birth newborn infants from HIV (Human Immunodeficiency Virus) infected mothers have to be subjected to prophylactic treatment against viral infection. HIV Integrase is the enzyme that mediates the integration of the viral genome into the host cells chromosomes and its catalytic prevention represents a major way to stop the viral infection. Despite its major clinical advantages (low toxicity compared to nucleotide analogs, lower effective IC50 and fewer adverse reactions than most protease inhibitors), the treatment with HIV Integrase inhibitors(INi) in newborns induces a paradoxical situation. Because HIV-IN resembles in its structure and reaction mechanism to Recombination Activating Gene protein RAG1, which assembles the lymphocytes antigen receptors, INi medication interferes with the ability of treated patients to develop a normal immune response. By reducing RAG activity (Melek, 2002), the currently used HIV-INi induce an iatrogenic immunodeficiency which mimics the onset of AIDS (acquired immune deficiency syndrome). This situation sometimes prompts at these treated patients a more aggressive therapy with higher medication doses, which in turn accentuates the aforementioned immunodeficiency. We propose to solve the major drawback of INi treatment that it cannot be addressed to newborns exposed to high risk acquiring HIV-1(type1) infections.The major goal of our proposal is to test new HIV specific Integrase inhibitory compounds which do not interfere with RAG somatic recombination. Our expertise with biophysical assays testing RAG activity is the key element ensuring the creativity and originality of this proposal. We propose to use a new strategy to separately screen for compounds inhibiting IN at each of its three integration steps: viral DNA-IN binding, catalytic 3' DNA nicking and strand Transfer. Nowadays, in drug discovery and screening strategies just one of these IN activities is targeted for potential inhibition. Based upon our results from our work investigating critical RAG-DNA binding/bending activity(Ciubotaru et. al, 2003, 2013) in somatic recombination, we propose to develop rapid, low cost, efficient fluorescence resonance energy transfer (FRET) setups and screening assays some at single molecule level. With them we will high-throughput screen(HTPS) our in silico designed and derivatized library of HIV Integrase inhibitory compounds for their in vitro dual HIV Integrase inhibition and RAG activity interference effects. Dual screening for IN inhibition with no RAG activity interference is unprecedented and represents an entirely original approach for the development of this family of drugs. The FRET in vitro screened compounds will be quantitatively tested for their effect on RAG mediated DNA substrate cleavage reactions. The lead compounds will then be tested in a primary cell line culture screening assay. We will test their cell toxicity and their potential inhibitory effect on stage progression from pre B to immature B lymphocyte(which requires somatic recombination). This will be assessed by cell survival and preB/IgM surface markers display. The best candidate compounds screened by our assays will be further tested for their potential to interfere with antigen activation of B cells from biopsies of immunocompromised lymphoma patients. For this, the compounds will be added on lymphomatous B cells cultures with LPS (Gram Negative Bacterial Lipopolysaccharide) and Interleukin 4 (IL4) and their effect tested by proliferation tests directed against control cell cultures without drugs. Our selected lead compounds should not affect patients immunity, hence after future tests in animals and in patient clinical trial studies they should reach the highest marketing potential among all other drugs from their class.
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Regression-based theranostic polyfactorial classifier for melanoma patients stratification
Call name:
Joint Applied Research Projects - PCCA 2013 - call
PN-II-PT-PCCA-2013-4-1407
2014
-
2017
Role in this project:
Key expert
Coordinating institution:
SPITALUL CLINIC "COLENTINA" BUCURESTI
Project partners:
SPITALUL CLINIC "COLENTINA" BUCURESTI (RO); INSTITUTUL NATIONAL DE CERCETARE-DEZVOLTARE IN DOMENIUL PATOLOGIEI SI STIINTELOR BIOMEDICALE "VICTOR BABES" RA (RO); CENTRUL MEDICAL CAROL SRL (RO)
Affiliation:
SPITALUL CLINIC "COLENTINA" BUCURESTI (RO)
Project website:
http://www.cdpcolentina.ro/01%20meltag.html
Abstract:
Cutaneous melanoma is a disease with increasing incidence worldwide; it is a malignancy with unfavorable prognosis, causing important human and economic losses; the current staging of patients with melanoma (AJCC 2009) has poor predictive value, identifying new biomarkers being mandatory.
Regression in melanoma is a morphological parameter credited by various authors with favorable or unfavorable prognostic significance. Our previous studies have shown that there are different processes of regression in melanoma (both morphologically and as type of inflammatory infiltrate) and regression in melanoma is expression of intratumor heterogeneity, areas with regression presenting, in some tumor subcategories, variations in expression of some biomolecules associated with favorable prognostic significance.
We propose a detailed genomic and proteomic study of melanomas with regression that has as main objective establishing of polyfactorial classifier for diagnosis/ prognosis/ therapeutic approaches in melanoma. As secondary objectives are the establishing and validation of serum and tissue biomarkers in melanoma and the identification of mechanisms involved in melanomagenesis and tumor progression.
To reach these objectives, we will select cases well documented for clinic data and follow-up. We will analyze minimum 45 melanomas with regression (areas with and without regression), minimum 45 melanomas without regression and, as control, benign melanocytic lesions with regression (minimum 28 nevi with halo) / no regression (minimum 28 common nevi). These cases will be selected from the archives of CO, a university hospital with solid reputation in dermatology and dermatopathology, and, when possible, from those of P2.
We will identify areas of interest on paraffin embedded fragments and we will dissect them under microscopic control; the obtained material will be analyzed by arrayCGH (P1). We analyze the products of mutant gene both in tissue (CO) and serum (P1) by immunohistochemical techniques, proteomics technologies and protein microarray. We will perform an extensive statistical analysis of genomic and proteomic data for selecting biochemical, immunohistochemical and genetic parameters significantly associated with prognosis. It will therefore establish the theranostic polyfactorial classifier. The new classifier will be further validated on a separate group of patients using serum, frozen tissue and paraffin blocks from CO and P2, kept in P1 tissue bank. For validation, we will use biochemical and IHC tests (proteomic biomarkers) and more accessible molecular methods (qPCR/FISH) (genomic biomarkers).
Our results will be disseminated widely through presentations (poster/oral presentations) in national/international congresses/symposia, scientific articles (indexed journals) and a workshop. We will apply for a national patent for the classifier.
The consortium includes a university hospital - CO with wide addressability and modern equipment for histopathology, a research institute - P1 with solid reputation in circulating biomarkers identification and genetic analysis and a SME - P2 with dermatooncologic medical profile. The teams are multidisciplinary (dermatologists, pathologists, biochemists, biologists, geneticists, laboratory medicine physicians, statisticians) including senior and junior researchers. We will create new positions (PhD / postdocs). Consortium selection was based on complementarities between institutional partners and synergies between them and SME to achieve both SME involvement in research and technology transfer between academia, public health sector and SME medical private practice.
Our study will lead to valuable results for both health system (early diagnosis) and individual patients (personalized therapy). The polyfactorial classifier for melanoma diagnosis, prognosis and treatment monitoring will generate other national patents for biomarkers in melanoma.
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V(D)J recombination targeted in cis by transcription induced DNA supercoiling.
Call name:
Complex Exploratory Research Projects - PCCE-2011 call
PN-II-ID-PCCE-2011-2-0024
2012
-
2016
Role in this project:
Coordinating institution:
Institutul National de Cercetare-Dezoltare pentru Fizica si Inginerie Nucleara "Horia Hulubei" (CO)
Project partners:
Institutul National de Cercetare-Dezoltare pentru Fizica si Inginerie Nucleara "Horia Hulubei" (CO) (RO); Institute of Biochemistry of the Romanian Academy (P) (RO)
Affiliation:
Institutul National de Cercetare-Dezoltare pentru Fizica si Inginerie Nucleara "Horia Hulubei" (CO) (RO)
Project website:
http://proiecte.nipne.ro/pn2/149-proiecte.html
Abstract:
Somatic recombination assembles and diversifies the antigen receptor genes, of B and T cells. RAG recombinase binds two specific DNA sites (RSSs) to initiate recombination, a process called paired complex (PC) or synapsis formation. Synapsis is followed by cleavage and then by repair of the double stranded breaks which physiologically occur only between gene segments located intrachromosomally. Pairing preserves the integrity of the genome, preventing aberrant interchromosomal joinings (translocations) implicated in human B and T cell lymphomas. More than half of all childhood cancers derive from lymphoid cells and most of these malignancies are due to aberrant recombination translocations. Despite its significance the mechanism that physiologically directs somatic recombination for sites located in cis with respect to DNA is entirely unknown. Prior to recombination, dechromatinization, and germline transcription of the variable gene segments of the immunoglobulin (Ig) or T cell receptor (TCR) loci leads to a substantial dynamic change in the torsional tension and supercoiling of the adjacent DNA (2-7). This project studies the role of DNA supercoiling as an active factor in controlling RAG intrachromosomal sites pairing. Using DNA circles containing RSS sites of defined topology, we will study how is the rate and efficiency of RAG synapsis affected by their configuration. To supercoil the DNA subjected to recombination and to test in vivo the targeting mechanism we will use heterologous controllable transcription units in the proximity of reporter RSSs. The knowledge of RAG preferred RSS topology allows us to develop an unprecedented experimental way to induce in vivo targeted chromosomal translocations and with it we propose to test potential pharmacological agents to block such aberrant reactions.
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FILE DESCRIPTION
DOCUMENT
List of research grants as project coordinator or partner team leader
Significant R&D projects for enterprises, as project manager
R&D activities in enterprises
Peer-review activity for international programs/projects
[T: 0.3591, O: 184]