University of Zagreb

School of Medicine

The Knowledge Transfer and Innovations Office, as a part of the Centre for Translational and Clinical Research (Centre, CTCR), provides professional support to basic, translational, and clinical research conducted by the staff and students of the University of Zagreb School of Medicine and University Hospital Centre Zagreb.
The Office supports scientists in writing project proposals and implementing research projects, assists in the valorization of intellectual property, protection of IP rights, and the transfer of knowledge and technologies for both commercial non-commercial purposes. The main objective of the Office is to find the best and fastest way from research results to the end users - patients.
Through its experience in clinical research, the Office is a unique place for support of clinicians who perform highly regulated research involving patients.

The Centre performs and provides the following activities and services:

Intellectual property protection and technology transfer:

Project proposals’ preparation and implementation of projects:

• Teaching scientists and students in the field of intellectual property and technology transfer;
• Encouraging the protection of intellectual property and its use;
• Supporting researchers in identifying and protecting intellectual property;
• Evaluation and assessment of the commercial potential of inventions and other research results, alone or in collaboration with the University Technology Transfer Office and other external experts;
• Preparation and revision of non-disclosure and material transfer agreements;
• Negotiating, organizing, and coordinating cooperation with industry;
• Preparation and review of draft agreements with industry in cooperation with the School Legal department;
• Preparation of draft licensing and assignment agreements, and other contracts related to intellectual property and its transfer;
• Participation in establishing the spin-off companies in cooperation with the Legal Department and external experts and negotiating of shares in the newly created companies;
• Keeping records of the School’s intellectual property, patents, licensing agreements and other forms of protected and unprotected intellectual property, commercialisation contracts and non-commercial forms of exploitation of intellectual property results;
• In the complex collaborative research environment, the Office helps in the preparation and reviewing of cooperation agreements (with one or more partners), clinical research contracts, and other agreements containing clauses on intellectual property rights, access rights, and other rights related to knowledge or technology transfer.

• Supports the preparation of international project applications, in particular in regard with knowledge transfer and the exploitation and sustainability of research results;
• Participates in the implementation of the projects, in particular in the exploitation of the results;
• Participates in the implementation of projects aimed on strengthening capacity of the institution and increase of knowledge and technology transfer activities;
• Helps in project management and education of newly employed research managers and administrators.

Other activities:

• Active in the Committee for Intellectual Property Management;
• Collaboration with the Centre for Research, Development and Technology Transfer of the University of Zagreb on various joint activities;
• Member of the ASTP (Europe’s Association of Knowledge Transfer Professionals);
• Participation in the work of EATRIS ERIC, European Research Infrastructure

Contact

The Department of Intercellular Communication (DIC) was founded as a spin-out of the pharmaceutical industry within the academic community, in order to foster close collaboration between these complementary but often insufficiently integrated research activities. To encourage translational research in the field of new drug discovery, GlaxoSmithKline (GSK) Research Centre Zagreb, together with the School of Medicine invested in adapting the space and equipping the DIC and provided educated and experienced staff to co-founders.

The main activity and current interest of the Department is the study of coexistence, interaction and mutual regulation of different microbial communities (microbiota) and their host, with the aim of broadening the knowledge on the role of these processes in maintenance of human health and in pathogenesis of infectious and inflammatory diseases. The integration of the scientific knowledge into clinical practice is of high importance, as it can contribute to improved diagnostics in infectious and inflammatory diseases, as well as to more efficient treatment strategies and the development of more effective targeted drugs. Therefore, understanding the subtle interactions that regulate the host-microbiota relationship or lead to progression into pathogenic conditions is the main scientific interest of the Department staff.

DIC scientists have many years of work experience in the pharmaceutical industry (PLIVA Research Institute and GlaxoSmithKline Research Centre) as a part of numerous R&D projects for developing new drugs. The researchers have extensive expertise in the fields of molecular biology, cell biology, microbiology and the development of new research methods. They also have knowledge related to the broader context of the development of new drugs, the discovery of new biological targets, the protection of intellectual property and the management of scientific projects. The knowledge and experience accumulated in the Department are employed for the development of potential new therapies and clinical strategies and interventions, and thus contribute to the advancement of clinical and translational medicine.

The Department cooperates with relevant scientific institutions and research groups in the country and abroad. Employees of the Department actively participate as expert evaluators of research projects submitted to the EU, international and domestic competitions in the field of science, innovation and economy.

Scientific projects:

• MINUTE for IBD (HRZZ)
• PROBITECT (IRI)
• MaCrovid (Zaklada Adris)
• OSTEOGROW (FP7)
• OSTEOproSPINE (Horizon 2020)
• Center of Excellence for Regenerative and Reproductive Medicine
• Projekt razvoja karijera mladih istraživača (HRZZ)

Head

Staff

The Department for Functional Genomics was founded in 2003 by School of Medicine University of Zagreb, the University Hospital Centre Zagreb and the scientists of Harvard Medical School as a scientific centre intended to encourage translational research using advanced genomic technologies (then called the Centre for Functional Genomics). As the first such centre in the field of South-eastern Europe, the Centre for Functional Genomics has laid the foundations for the creation and establishment of a Centre for Translational and Clinical Research. When the Centre for Translation and Clinical Research was established in 2009, the Centre for Functional Genomics was renamed into the Department for Functional Genomics. Since the very beginning of the Department's activities, great importance has been devoted to the development of international cooperation, resulting in joint projects and programmes with scientists from Harvard University and New York University from the United States, as well as with numerous scientific institutions across Europe, such as the Institute for Molecular medicine (Portugal), the Medical Research Council Human Genetics Unit (UK), University College Dublin (Ireland) or Ludwig-Maximilians Universität München (Germany).

Scientific activity within the Department is aimed at connecting basic and clinical scientists in modern genomic research with the aim of promoting translational approaches. Over the years, numerous investigations have been conducted within the Department, from gene expression research in cognitive disorders, search for new biomarkers for neurodegenerative diseases, to research on molecular basis of haematological and autoimmune diseases.

Projects implemented so far in the Department for Functional Genomics have been financed by the European Union, the World Bank, the Croatian Ministry of Science and Education, the Croatian Science Foundation, Michael J. Fox Foundation, Parkinson's UK Foundation, ADRIS Foundation, DAAD and HAMAG/BICRO. The Department's scientific activities have also led to clinical application of new genomic diagnostic tests in practice. With great effort from employees, the list of genomic diagnostic tests includes:

• epilepsy gene panel (DTP code LG206),
• array CGH (LG207 and LG 208),
• clinical exome sequencing (LG235).

Scientists from the Department provided significant resources for research through scientific projects, both from domestic funding sources (e.g. Ministry of Science and Education project “Genomic analysis of transcripts and interactome in patients with complex diseases”), as well as from EU funds, through Framework Programme 7. The EU project entitled “Integrating and Strengthening Genomic Research in South-Eastern Europe” (INTEGERS) is the first FP7 project in the Republic of Croatia. The allocation ensured that the Department becomes the best equipped centre for genomic technologies in the Southeast European region.

Head

Staff

The Department for Reproduction and Development Research started its activities in 2009, and its scientific and research activity resulted from the collaborative project of Ministry of Science, Education and Sport, which at the time brought together nine individual scientific and research projects. In accordance with the action plan of the School of Medicine, and according to the research strategy of the University of Zagreb, a proposal was made for a translational program in the field of reproduction and development in the form of 22 scientific and research tasks proposed by individual leaders. At its session held on 27 January 2009, the Faculty Council of the  University of Zagreb School of Medicine adopted the proposal for the abovementioned translational programme.

The programme is implemented in over 30 domestic collaborative health institutions. 24 prestigious international institutions are also participating in the programme. The central working group consists of the employees of the Research Department of Histology of the School of Medicine and the Urology and Gynecology and Obstetrics departments of the University Hospital Centre Zagreb.

In addition to the standard activities related to certain scientific and research tasks, the Department initiated the introduction of new health services in the field of medical insemination in the public health system of the Republic of Croatia, which would be jointly provided by the School of Medicine and University Hospital Centre Zagreb: establishment and registration of seed biopsy bank (at the level of the Republic of Croatia) and Centre for Andrology within the Urology Department. Work is under way on the refurbishment of premises and the procurement of equipment for the Bank and the Centre, and it is expected that the Ministry of Health will grant a license for work.

Head

Staff

• Prof. Davor Ježek, MD, PhD
• Prof. Ljerka Banek, MD, PhD
• Prof. Đurđica Grbeša, MD, PhD
• Prof. Gordana Jurić-Lukić, MD, PhD
• Asst. Prof. Željka Vukelić, PhD
• Andreja Vukasović, dMD
• Željka Punčec, med. lab. ing.
• Mirela Vranić, bacc. med. lab. ing.
• Iris Elezović, med. lab. ing.
• Adriana Čuljak
• Goran Kapustić

Proteins play important roles in cells and tissues in maintaining structural integrity, catalysing numerous biological processes, and regulating gene expression. Proteomics is a scientific discipline that studies the structure, function, and interactions of cellular proteins. Unlike the genome, which is relatively simpler and easier to define, a proteome is a set of all proteins that is significantly more complex due to numerous protein isoforms and post-translational modifications. Additionally, the variability in size among proteins, their temporal, and spatial expression patterns and their broad dynamic range of expression, each pose unique difficulties in defining the proteome of a biological system.

The Department for Proteomics operates at the Centre for Translational and Clinical Research. The core activities of the Department include the development and implementation of proteomic methods that systematically study the structure and function of proteins. Depending on the sample types, they can be used to examine the total proteome of an organism, an individual organ, a specific signalling pathway, or individual cells, but also a detailed study of the structure of single purified proteins.

The basic research areas of the Department for Proteomics include:

• Defining potential biomarkers and therapeutic targets for rare bone diseases, bone fractures and delayed fracture healing;
• Upgrading the platform for bone regeneration using new autologous formulations;
• Exploring the potential and validating novel biomarkers (detected by proteomics) in tracking disease progression and prognosis in various tumour conditions;
• Inflammageing as a key component underlying various pathological changes and regeneration (the connection between fibrosis and different pathological processes: liver, kidney and skin disease)
• Defining the status and validation of new markers (biomarkers)

The use of mass spectrometry-based proteomics in the field of biomedicine implies the translation of knowledge from basic research to clinical applications. Direct application of newly acquired knowledge can guide and fine-tune clinical decisions and interventions. In practical terms, this comprises comparing the proteomic profiles of individual tissues (or biological fluids) of healthy versus diseased patients, and the detection of potential differences in the expression level of select target proteins.

Department from 2008 until today

The Department for Proteomics was founded on 10 June 10 2008. The initial head of the Department was academician Slobodan Vukičević, with his associates at the time Prof. Lovorka Grgurević, MD, PhD, and consultant Dr. Boris Maček (then at Max Planck Institute of Biochemistry, Martinsried, Germany). Since 2016, Prof. Lovorka Grgurević, MD, PhD has become the Department together with her closest associate and employee of the Department, Ruđer Novak, PhD, and associates: Stela Hrkač, MD, Grgur Salai, MD, and student Joško Bilandžić.

Where are we?

The Department for Proteomics is located in the 2^nd floor at Šalata 2, in two laboratories and two office spaces. The preparatory laboratory has an area of ​​about 15 square meters, the analytical LC-MS laboratory has an area of ​​about 48 square meters, and the office spaces of 15 and 30 square meters.

What can we offer?

• Consultations on experimental design;
• Sample preparation (extraction of proteins from plasma, serum, saliva, cerebrospinal fluid, cells, tissues, or tissues fixed by formalin; protein digestion, sample preparation for a bottom-up proteomic approach);
• Liquid chromatography and mass spectrometry (proteomic approach or sequencing of individual proteins);
• Western blot, ELISA, isoelectric focusing;
• Data processing and bioinformatics analysis;
• Interpretation of experimental results;
• Scientific education of a new generation of researchers in the field of functional proteomics.

Equipment

• Thermo Scientific LTQ Orbitrap Discovery. As key devices of the Department for Proteomics, with the wholehearted help of the University Hospital Centre Zagreb, School of Medicine and the Ministry of Science, in 2008 a state-of-the-art high-resolution mass spectrometer LTQ Orbitrap Discovery (Thermo Fisher Scientific) was purchased and is predominantly used for characterization of a large number of proteins and peptides in various diseases and pharmacokinetic research;
• HPLC ThermoScientific UltiMate 3000;
• Standard electrophoresis equipment (SDS PAGE, Western blot) including horizontal isoelectric focusing system Serva HPE Blue horizon;
• Small laboratory equipment (cooling centrifuges, vacuum evaporator, thermoblocks, etc.)

Collaborations

Since 2016, the Department has been intensively working to achieve its main goal – to promote the translation of knowledge by combining programs in basic and clinical medical research. In addition to biomedicine, some of our multidisciplinary collaborations are realized with research groups working in the field of biology and chemistry. The Department participates with significant contributions in the programs within the project Scientific Center of Excellence: Reproductive and Regenerative Medicine - Exploring New Platforms and Potentials, and OSTEOproSPINE - Novel Bone Regeneration Drug Osteogrow: Therapeutic Solution for Lumbar Back Pain", HORIZON 2020. It was also an integral part of OSTEOGROW - Novel Bone Morphogenetic Protein 6 Biocompatible Carrier Device for Bone Regeneration, FP7 HEALTH project and lead the research project funded by the Croatian Science Foundation "Newly discovered circulating BMP1 protein isoforms as biomarkers and therapeutic targets for human diseases" and numerous other scientific projects.

The services of the Department of Proteomics are available to all departments and laboratories within the School of Medicine, University of Zagreb. Our services are also available to all other academia members within the University of Zagreb and other Universities, to Ruđer Bošković Institute and hospital centres and other interested parties. As such, long-term fruitful cooperations have been established with the Ruđer Bošković Institute, the Faculty of Veterinary Medicine in Zagreb, the School of Dental Medicine in Zagreb, the University Hospital Centre Sestre Milosrdnice, University Hospital Dubrava, University Hospital Centre Zagreb, Childrens’ Hospital Zagreb, University Hospital for Tumors, University Hospital Merkur and private medical clinics. The Department works closely in terms of external consultation with Prof. Boris Maček, MD, PhD, head of the Proteome Center Tuebingen, University of Tuebingen.

Our role

The role of the Department for Proteomics within the Centre for Translational and Clinical Research is essential. The research of disease mechanisms is no longer focused and described by the action of single proteins, but by the complex interrelationships of multiple proteins on a global scale. In the "post-genomic" period, proteomic methods play an increasingly important role in understanding the pathophysiological basis of various diseases and discovering their diagnostic or prognostic markers.

This research can already guide or fine-tune clinical decisions and interventions, and, in the near future, routine identification of modified peptides and proteins associated to particular diseases is expected. The rising complexity of biomedical research requires close collaboration between basic and clinical scientists trained in the application of the latest technologies and knowledge, in order to improve human health and improve health care.

In addition, for many years, the Department for Proteomics participates in teaching several postgraduate courses at the Schools of Medicine and Dentistry, University of Zagreb. This way, the participants are introduced to the scientific method, and basic knowledge on the possibilities of proteomic research is transferred. Opportunity for new scientific collaborations is thus established, which is a special goal of the Department.

Due to all the above, the role and existence of departments for proteomics within all science-oriented research institutions is crucial.

Head

Staff

Associates

Stela Hrkač, MD
Grgur Salai, MD
Joško Bilandžić, student

The Laboratory for Mineralized Tissues, founded in 1986, has the longest tradition in the Centre for Translational and Clinical Research. Since then, the laboratory has expanded and is now equipped with all the equipment necessary for modern research. Laboratory animal facility (housing mice, rats, and rabbits) was registered in 2011 which enabled the breeding and husbandry of animals used in experimental research (approval from Directorate for Veterinary and Food Safety, Ministry of Agriculture).

Since 2007, research has been focused on the mechanism of action of bone morphogenetic proteins in tissues such as kidney, liver, and pancreas, as well as to the discovery of new biomarkers in various diseases. In the last couple of years, research topics also included the function of BMPs in iron and glucose metabolism and the effect of serotonin on the skeletal system.

Recently, the Laboratory was funded for multiple projects, some of which are the EU FP7 project OSTEOGROW, where the School of Medicine is the coordinator of a consortium of 11 partners; project OSTEOproSPINE (Horizon 2020) which is a continuation of the previous OSTEOGROW; a Scientific Center of Excellence for Reproductive and Regenerative Medicine project “Reproductive and regenerative medicine – exploration of new platforms and potentials” (KK.01.1.1.01.0008); and the “BMP6Fe3 – Development of novel antibodies (biologics) that will selectively inhibit hepcidin expression in the liver for the Treatment of Anemia of Chronic Disease” project funded by the Croatian Science Foundation. The Laboratory is continually cooperating with many Croatian and international scientific institutions. A large number of published papers and PhD dissertations, which are the result of consistent devoted work in this Laboratory, demonstrate its important role in scientific research in Croatia.

Discovery of the structure and function of genes and proteins from the super family TGF-beta

Years of research in collaboration with world-renowned laboratories have resulted in numerous studies and led to the clinical application of recombinant bone morphogenetic proteins in human medicine to accelerate and promote bone formation in patients with spinal pathologies, acute and non-union fractures. More than 30,000 patients worldwide have been successfully surgically treated with bone morphogenetic proteins (BMP). The role of BMPs in bone, kidney, and articular cartilage regeneration has been extensively investigated, and the foundations for BMP7 use in patients with acute and chronic renal failure have been laid. In addition, within the projects OSTEOGROW and OSTEOproSPINE in cooperation with clinics in Croatia and Austria, clinical studies of BMP6 are conducted in several orthopedic indications. This complex field of research has become a major area of ​​research in the Laboratory and has resulted in more than 4,200 citations in the works of other scientists.

The most important contributions of the Laboratory of Science in the field of BMP are:

• Discovery of cartilaginous morphogenetic proteins (CDMP-1, -2 and - 3; also called GDF-5, -6 and -7 or BMP12, -13 and -14) and prostate proteins (PDF; also called BMP11)
• Purification and in vitro role of BMPs to demonstrate their ability to differentiate osteoblast precursor cells into fully differentiated osteoblasts and to redirect the inhibitory effect of TGF-beta on cell differentiation. The same principle was later confirmed in collaboration with scientists from the Universities of Leiden and Bern as the main mechanism by which TGF-beta induces the transformation of epithelium into mesenchyme in prostate and breast cancer
• Characterization of tissues and organs that produce bone morphogenetic proteins at the level of mRNA and proteins during embryonic development as well as in postnatal life
• Systemic application of BMP6 restores bone volume and microarchitecture in old ovariectomized rats by increasing bone structure and inhibiting bone resorption
• Discovery of various isoforms of BMP1 protein (mTld metalloproteinase), primarily BMP1-3 isoforms, and its effect on fibrosis

OSTEOGROW – new formulations

New formulations of OSTEOGROW (rhBMP6 in autologous blood coagulum as a carrier) are being investigated as part of the research on the regenerative role of rhBMP6. Part of the research efforts are invested in the examination of longevity of newly formed bone by addition of bisphosphonates. The potential clinical application of the mentioned OSTEOGROW formulations is being investigated in a model of posterolateral spinal fusion in rabbits and sheep. Preclinical studies have shown numerous advantages of OSTEOGROW formulations.

The role of BMP3 in bone tissue formation and regeneration

One of the research topics in the Laboratory is the role of bone morphogenetic protein-3 in bone tissue, a divergent member of BMP protein family that antagonizes the effect of other BMPs. Even though it is the most abundant protein in bone tissue from this family, BMP3-related research is insufficient. Until now, neither its effect on bone regeneration nor its interplay with osteogenic BMP6 have been studied. For this research, in vitro models are being used, including bone marrow mesenchymal stem cells and C2C12 and MC3T3 cell lines, as well as BMP3 knockout mice. In vivo research focuses on BMP3 effect on ectopic bone formation and fracture healing.

Antifibrosis therapy in congenital muscular dystrophy with mutation in laminin gene in a mouse model

Congenital muscular dystrophy with merosin deficiency (MDC1A) is an autosomal recessive form of muscular dystrophy characterized by muscle weakness visible at birth or in the first six months of life and is the second most common type of muscular dystrophy. This form of muscular dystrophy often has a very aggressive pathology and in many cases can lead to premature death in children due to respiratory problems and due to slow progression and growth. At the moment, there is no effective therapy that would have a positive effect on this disease and therefore there is a desire to identify the best and most successful treatment. Lama2 DyW is a mouse model for congenital muscular dystrophy with a mutation in laminin gene used in this research work. Mice reside in controlled conditions (temperature, pressure, humidity, ventilation, day and night cycle) in a special ventilated cabinets. This mouse strain is very sensitive and homozygous individuals live up to four weeks so the experiments had to be strategically and carefully prepared and planned. Mice with antifibrosis treatment (inhibition of BMP1-3 proteins with specific antibodies) show excellent results at the biochemical, histological and behavioural levels and we hope that the future will bring many excellent results. The results of this research could enable the development of a new targeted therapy for a condition for which only empirical palliative solutions currently exist.

The impact of bone morphogenetic protein 6 (BMP6)

UThe role of bone morphogenetic protein 6 (BMP6) was previously determined in bone metabolism and nowadays many studies have demonstrated the effect of BMP6 in glucose metabolism and the development of type II diabetes. Serotonin (5HT) was found to act on the regulation of the endocrine function of the pancreas and bone metabolism. The involvement and the interaction between BMP6 and 5HT in bone and glucose metabolism have not been thoroughly investigated so far, and it is assumed that BMP6 and 5HT are in mutual interaction and have a synergistic effect on glucose metabolism, and consequently, on bone metabolism. In vitro, we will examine the effect of BMP6 and 5HT on cellular processes related to glucose metabolism, insulin secretion, and the 5HT system on the pancreatic endocrine cell line. Preliminary results indicate that BMP6 enhances the activity of the 5HT system in conditions of increased glucose concentration. In vivo, studies on glucose metabolism and changes in the 5HT system in the multiple organ systems in mice lacking BMP6 function (BMP6 knockout mice) are in course. The results of this research will enable observation of a functional association between BMP6 and 5HT in bone and glucose metabolism, contributing to a better understanding of their role in systemic biology as well as enabling research of new strategies for treating diabetes.

The role of dentin matrix protein 1 (DMP1) in bone formation and regeneration

The potential role of DMP1, the molecule responsible for dentin formation, in bone regeneration and formation processes is being investigated. The study is performed on preosteoblast mouse cells (MC3T3). Potential contribution of DMP1 is also tested in vivo in a subcutaneous assay and in fracture healing. The research is conducted in collaboration with the Chicago College of Dentistry (University of Illinois, Chicago, USA).

Collaboration with other laboratories

The employees of the Laboratory cooperate on numerous projects in and outside the Republic of Croatia. The micro-CT device, available in the Laboratory, forms the basis of the study of mineralized tissues because it allows detailed visualization and quantification of bone parameters. The Laboratory for Mineralized Tissues has collaborated on projects of the University of Zagreb BioCOMET, BioCHIP and HIPoCART and in collaboration with the Faculty of Medicine, University of Rijeka.

Head

Staff

• academician Slobodan Vukičević, PhD, head of the Laboratory
• Prof. Lovorka Grgurević, MD, PhD
• Vera Kufner, PhD, research associate
• Igor Erjavec, PhD, research associate
• Tatjana Bordukalo Nikšić, PhD, research associate
• Nikola Štoković, PhD, assistant
• Natalia Ivanjko, mag. ing. biotechn., PhD student, assistant
• Ivona Matić Jelić, mag. chem., PhD student, assistant
• Viktorija Rumenović, mag. mol. biol., PhD student, assistant
• Kristian Bakić , mag. ing. chem. ing., PhD student, assistant
• Marina Milešević, mag. ing. biotechn., PhD student, assistant
• Ivana Sataić, PhD, professional associate
• Lucija Rogina, mag. ing. tech. aliment., PhD student, professional associate
• Valentina Blažević, mag. ing. biotechn., professional associate
• Sanja Pehar, mag. mol. biol., professional associate
• Ivančica Bastalić, prof., personal assistant
• Romana Blažek, secretary
• Đurđica Car, technician
• Mirjana Marija Renić, technician

A novel anabolic targeted therapy for osteoporosis: BONE6-BIS consortium

January 1^st 2012 – December 31^st 2014

PROJECT INFORMATION

Purpose

The purpose of the project is to develop a new therapeutic, BONE6-BIS, which will represent an efficient and safe drug for the treatment of osteoporosis. BONE6-BIS is a “chimeric” molecule which consists of a Bone Morphogenetic Protein 6 (BMP6) and bisphosphonate. Bisphosphonate, a small molecule, targets the molecule to the bone surface where BMP6 would exert its action and induce bone regeneration.

Disease and current treatments

Osteoporosis, which literally means “porous bones,” is a disease characterized by a reduction in bone density. Osteoporosis occurs when the normal repeating cycle of osteoclast (bone resorption) and osteoblast (bone formation) activity is misaligned resulting in bone resorption being greater than formation.  This process leaves the bones brittle and prone to fracture spontaneously or after a minor accident, with the spine, wrists and hips being most susceptible. Unfortunately, osteoporosis is a silent disease and can progress painlessly for years until a severe injury occurs. According to the National Osteoporosis Foundation (NOF), osteoporosis is a major health threat to 55% of people age 50 and over. While it’s a largely preventable disease, there is no cure.

There are several prescription medications used to treat osteoporosis. Bisphosphonates are the most commonly prescribed drugs for treatment of osteoporosis; they accumulate in bone matrix and can slow bone loss and increase bone density thus reducing the risk of fracture. Drugs called selective estrogen receptor modulators (SERMs) can act like estrogen to help prevent bone loss. Calcitonin, a hormone that your body naturally produces, may also be taken to help slow bone loss for some patients. Hormone or estrogen replacement therapy may also help prevent osteoporosis in postmenopausal women.

Goal

We have recently discovered that BMP6 may have specific therapeutic advantages as compared to other BMP family members in inducing regeneration of bone, pancreatic β-islets and kidney tubule epithelium. We demonstrated that BMP6 increases the bone volume when administered systemically to ovariectomized aged rats. In this project we will, for the first time, thoroughly characterize the naturally occurring BMP forms and complexes in blood and develop reliable assays for quantifying BMP6 in plasma and then express recombinant human (rh)BMP6 in its natural form.

Following production of rhBMP6 we aim to develop a novel anabolic therapy for osteoporosis via targeting rhBMP6 to bone surfaces by attaching it to a bisphosphonate which can be cross-linked to the protein via lysine residues.

PROJECT PARTICIPANTS

Project Leader – Professor Slobodan Vukičević, MD, PhD

Center for Translational and Clinical Research, School of Medicine, University of Zagreb
Assistant Professor Lovorka Grgurević, MD, PhD
Assistant Professor Donatella Verbanac, PhD
Jelena Brkljačić, BSc
Genadij Razdorov, BSc
Martina Pauk, BSc
Igor Erjavec, BSc

Genera Research
Hermann Oppermann, MD, PhD
Morana Jankolija, BSc
Anamarija Olić, BSc
Irena Popek, BSc
Marina Martinić, BSc

Clinical Hospital Center Zagreb
Assistant Professor Zlatko Giljević, MD, PhD
Assistant Professor Mislav Jelić, MD,PhD
Professor Darko Antičević, MD,PhD
Mislav Cerovec, MD,PhD
Živka Dika, MD,PhD
Antonio Cipčić, BSc

Croatian Academy of Science and Arts
Academy member Marko Pećina, MD, PhD
Igor Borić, MD, PhD

FUNDING

This project is funded by Croatian Science Foundation.

Total funding: 1.439.800,00 HRK

NEWS

22^nd March 2012

Lecture invitation

22^nd October 2012

PUBLICATIONS

Prior Art

Vukicevic S, Grgurevic L. BMP-6 and mesenchymal stem cell differentiation. Cytokine Growth Factor Rev 20:441-8, 2009.

Simic P, Culej JB, Orlic I, Grgurevic L, Draca N, Spaventi R, Vukicevic S. Systemically administered bone morphogenetic protein-6 restores bone in aged ovariectomized rats by increasing bone formation and suppressing bone resorption. J Biol Chem 281:25509-21, 2006.

USEFUL LINKS

Croatian Science Foundation: http://www.hrzz.hr/

Croatian Ministry of Science, Education and Sports: http://public.mzos.hr/

European Calcified Tissue Society: http://www.ectsoc.org/

International Osteoporosis Foundation: http://www.iofbonehealth.org/

National Osteoporosis Foundation: http://www.nof.org/

Assessment of Microbiota, Inflammatory Markers, Nutritional and Endocrinological Status in IBD Patients

Acronym: MINUTE for IBD

September 1st 2014 – August 31st 2018

SAŽETAK

Upalna bolest crijeva (IBD) predstavlja kronični proces u probavnom traktu sa sve većom učestalošću, koji značajno pogoršava kvalitetu života pacijenata. Nastanak bolesti  povezan je s imunim statusom, sastavom crijevne mikrobiote te unosom hrane. Trenutne znanstvene spoznaje o specifičnim pokretačima i dijagnostičkim markerima bolesti su ograničene, te su za bolje razumijevanje patofiziologije IBD neophodne nove informacije o sastavu crijevne mikrobiote, imunom, endokrinom i prehrambenom statusu pacijenata.

Projektom će biti detaljno istražena crijevna mikrobiota u uzorcima biopsije crijeva, stolice i krvi od 40 novo-dijagnosticiranih IBD pacijenata i 20 ne-IBD pojedinaca, kao i nutritivni i endokrini sastav svakog ispitanika. Za proučavanje sastava mikroorganizama iz uzoraka bit će korištena metoda sekvenciranja nove generacije, dok će u svrhu detekcije biomarkera iz krvi biti korištena vrlo osjetljiva metoda proximity extension assay (PEA). Dobiveni će rezultati omogućiti bolju stratifikaciju IBD pacijenata te ih lakše usmjeriti prema odgovarajućoj terapiji sukladno principima personaliziranog pristupa.

ABSTRACT

 Inflammatory bowel disease (IBD) is a chronic gastrointestinal disorder with increase in incidence that severely deteriorates patients’ quality of life. The onset of the disease is mainly associated with the immune status, gut microbiota and food intake. The current scientific knowledge of specific triggers and diagnostic markers is limited; therefore, new data on gut microbiota, inflammatory, endocrine and nutritional status are required to better understand the IBD pathophysiology.

In this study we will thoroughly explore host-gut microbiota interactions in order to define novel strategies for management of IBD. We will collect intestine biopsies, stool and blood samples from 40 newly diagnosed IBD patients and 20 non-IBD control individuals, as well as record their nutritional status. Since majority of the gut microorganisms are not culturable, we will use the in house available next-generation sequencing to characterize the composition of the microbiota in collected samples. Moreover, specific blood biomarkers, including cytokines, growth factors and hormones, will be determined using novel and highly sensitive proximity extension assays, recently developed in our laboratories. Collectively, these results will support better stratification of patients and initiate an appropriate therapy.

PROJECT PARTICIPANTS

University of Zagreb School of Medicine

Project leader – Assistant Professor Donatella Verbanac, PhD

Mihaela Perić, PhD

Mario Matijašić, PhD

Hana Čipčić Paljetak, PhD

Vera Kufner, PhD

Marina Panek, mag.biol.mol.

University Hospital Centre Zagreb

Associate Professor Željko Krznarić, MD, PhD

Assistant Professor Silvija Čuković Čavka, MD, PhD

Marko Brinar, MD, PhD

Nikša Turk, MD, PhD

Assistant Professor Darija Vranešić, PhD

Mirjana Kalauz, MD, PhD

Ivana Kraljević, PhD

Dina Ljubas Kelečić, mag.pharm

Ana Kunović, MD

Dora Grgić, MD

Associate Professor Dunja Rogić, PhD

University Hospital Dubrava

Marija Crnčević Urek, MD, PhD

Associate Professor Marko Banić, MD, PhD

Fidelta Ltd. Zagreb

Karmen Brajša, PhD

Xellia Ltd. Zagreb

Gabrijela Ergović, PhD

Imperial College London

Anja Barešić, PhD

FUNDING

This project is funded by the Croatian Science Foundation.

Total funding: 998.400,00 HRK

SCIENTIFIC PAPERS PUBLISHED

1. Meštrović T, Matijašić M, Perić M, Čipčić Paljetak H, Barešić A, Verbanac D. The Role of Gut, Vaginal, and Urinary Microbiome in Urinary Tract Infections: From Bench to Bedside. Diagnostics (Basel). 2020 Dec 22;11(1):E7. doi: 10.3390/diagnostics11010007.

2. Matijašić M, Meštrović T, Paljetak HČ, Perić M, Barešić A, Verbanac D. Gut Microbiota beyond Bacteria-Mycobiome, Virome, Archaeome, and Eukaryotic Parasites in IBD.  Int J Mol Sci. 2020 Apr 11;21(8):2668. doi: 10.3390/ijms21082668.

3. Leskovar D, Meštrović T, Barešić A, Kraljević I, Panek M, Paljetak HČ, Perić M, Matijašić M, Rogić D, Barišić A, Kelečić DL, Bender DV, Krznarić Ž, Verbanac D. The Role of Vitamin D in Inflammatory Bowel Disease - Assessing Therapeutic and Preventive Potential of Supplementation and Food Fortification. Food Tech Biotech 2018, 56(4), 455-463, DOI: 10.17113/ftb.56.04.18.5805

4. Panek M, Čipčić Paljetak H, Barešić A, Perić M, Matijašić M, Lojkić I, Vranešić Bender D, Krznarić Ž, Verbanac D. Methodology challenges in studying human gut microbiota - effects of collection, storage, DNA extraction and next generation sequencing technologies. Sci Rep. 2018 Mar 23;8(1):5143. doi: 10.1038/s41598-018-23296-4. (top 100 articles in Sci Rep for 2018)

5. Matijašić M, Meštrović T, Perić M, Čipčić Paljetak H, Panek M, Vranešić Bender D, Ljubas Kelečić D, Krznarić Ž, Verbanac D. Modulating Composition and Metabolic Activity of the Gut Microbiota in IBD Patients. Int. J. Mol. Sci. 2016, 17, 578; doi:10.3390/ijms17040578

Poveznica

Sinergijska inovativna kombinacija sastavnica mikrobiote kao osnova za razvoj inovativnih topikalnih proizvoda za tretiranje i prevenciju upalnih stanja humane kože - PROBITECT

August 16, 2020 – August 15, 2023

SURADNE INSTITUCIJE

PROTEKO d.o.o.

Mirta Mikulecky

Iva Ačkar

Tamara Kajfeš Hrgovan

Vanja Premzl

MEF

Mihaela Perić

Hana Čipčić Paljetak

Mario Matijašić

Dora Hrestak

Smiljka Vikić-Topić

Daniela Ledić Drvar

SAŽETAK

Atopijski dermatitis i sindrom osjetljive kože najčešća su kronična upalna stanja kože kod ljudi. Najnovija istraživanja ukazuju na velik značaj mikrobiote kože (svi živi mikroorganizmi na koži) na zdravlje kože. Kako bi se doprinijelo potrebama pacijenata i tržišta u sklopu projekta razvit će se topikalni pripravci na bazi humane mikrobiote, izuzetno dobrog profila dermatološke kompatibilnosti koji u odnosu na konvencionalne alternative nemaju nuspojava pri primjeni i koji se smiju koristiti bez recepta i nadzora liječnika te na taj način smanjuju financijsko opterećenje na zdravstveni sustav, a poboljšavaju kvalitetu života tih pacijenata.

Ciljne skupine projekta su: globalna populacija, pacijenti s kroničnim upalnim stanjima kože.

CILJ PROJEKTA

Cilj i svrha projekta je razviti proizvod do faze TLR 8 prema kojoj će isti biti na visokoj razini tehnološke spremnosti za komercijalizaciju na globalnom tržištu. Unutar projekta će biti razvijena nova inovativna formulacija topikalnog pripravka, riješeni tehnološki rizici i proizvodni problemi što će rezultirati topikalnim pripravcima na bazi humane mikrobiote i njihovih derivata, izuzetno dobrog profila klinički ispitane dermatološke biokompatibilnosti. Nova, inovativna znanstvena i tehnološka rješenja topikalnih pripravaka za pacijente s kroničnim upalnim stanjima kože kao atopijski dermatitis (AD) i sindrom osjetljive kože (SOK) bit će klinički testirana sa svrhom ispitivanja povećane učinkovitosti, smanjenja nuspojava te poboljšanja kvalitete života tih pacijenata u odnosu na konvencionalne alternative – lokalne kortikosteroide, te sa svrhom poboljšanja spektra djelovanja i time učinkovitosti u tretiranju AD u odnosu na dostupne alternative kortikosteroidima. Dodatnu tržišnu vrijednost predstavlja i njihovo planirano korištenje bez recepta i nadzora liječnika čime će se smanjiti financijsko opterećenje zdravstvenih sustava i poboljšati pristup pacijenata učinkovitim rješenjima za njihove tegobe. Obzirom na epidemiološke podatke, koristi od

formulacije za AD imat će do 20% populacije, a od formulacije za SOK 38 do čak 70% populacije. Radi se o stanjima koja su globalno prisutna pa učinkovita rješenja imaju i globalni potencijal.

FINANCIRANJE

HAMAG-BICRO, IRI projekt KK.01.2.1.02.0137

12.986.807,92 HRK

Molecular mechanisms of immune response and inflammasome activation in Parkinson's disease

15 Jan 2021 – 14 Jan 2025

PROJECT INFORMATION

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by proteinaceous aggregates and degeneration of dopaminergic neurons. The underlying mechanisms causing PD have not been fully elucidated. Persistent inflammation is a major aggravating factor in PD resulting in the loss of dopaminergic neurons. To date, several immune cell types have been shown to be responsible for driving PD progression. Dendritic cells (DCs) lie at the intersection of the immune response and the neurodegenerative process while T cell infiltration generates a harmful immune response. Additionally, there is a strong correlation between inflammasomes and neurodegeneration indicating a possible association between the autoimmune response and neuronal loss. The aim of the project is to identify and characterize underlying mechanisms of immune response and inflammasome activation in PD patients using genomic analyses in order to decipher the pathways involved in the immune system regulation. Furthermore, we will analyze potential protein biomarkers from blood involved in inflammatory pathways and correlate the results with gene expression analyses. The detected gene variants and differential expression profiles of selected immune cell subpopulations will further be characterized using cell lines, as well as in human brain samples. In particular, we will validate the immune response using the knockdown and overexpression approach in DC lines generated from PD patients and healthy controls. In addition, we aim to define the causal relationship between aSyn accumulation and the immune response by knockdown of identified genes in the SH-SY5Y cell line and primary cortical neurons. Finally, in order to validate our mechanicistic findings, the last step will be to perform immunohistochemistry experiments on human brain sections. The results of the project may help identify novel putative targets for development of neuroprotective treatments by modulating the immune response.

PROJECT PARTICIPANTS

Project Leader – Professor Fran Borovečki, MD, PhD

• Antonela Blažeković MD, PhD University of Zagreb School of Medicine
• Kristina Gotovac Jerčić PhD University Hospital Center Zagreb
• Filip Bingula Bacc. University of Zagreb School of Medicine
• Mario Matijašić PhD University of Zagreb School of Medicine
• Miroslav Mayer. Assistant prof. University Hospital Center Zagreb
• Srđana Telarović Prof. University Hospital Center Zagreb
• Helena Šarac MD, PhD University Hospital Center Zagreb
• Borislav Radić Assistant prof. University Hospital Center Zagreb
• Alemka Markotić Prof. University Hospital for Infectious Diseases "Dr. Fran Mihaljević"
• Lidija Cvetko Krajinović PhD University Hospital for Infectious Diseases "Dr. Fran Mihaljević"

FUNDING

This project is funded by Croatian Science Foundation.