Sveučilište u Zagrebu Medicinski fakultet

Unatoč dostignućima u razumijevanju važnosti moždanog izvanstaničnog matriksa (ECM, difuznog ili kondenziranog kao perineuronske mreže, PNN) za fiziološke i patološke procese u mozgu, on je još uvijek daleko manje prepoznat i istražen od staničnih elemenata. U cilju novih spoznaja o ključnim molekulama i razvojnim događajima u ECM-u, posebno onih koji su izraženi u ljudskom mozgu, istraživači sa HIIM-a u  Zagrebu i Tehničkog Sveučilišta u Dresdenu, s kliničarima-istraživačima s KBC Zagreb i AKH Sveučilišta u Beču će ujediniti znanstvene pristupe, modele (ljudski, štakorski i organoidi) i metodologije (histološke, molekularne, bihevioralne i magnetska rezonancija (MR) 3T i 7T) kako bi se odgovorilo na sljedeće znanstvene izazove: (1) otkriti značajne razlike u sastavnicama ECM-a između fetalnih zona, odjeljaka, aksonskih (strata) i kortikalnih (layers) slojeva; (2) otkriti vremensko-prostorne obrasce ekspresije molekula ECM-a telencefaličke stijenke i bazalnih ganglija u razvitku i definirati ključne vremenske točke ireverzibilnih promjena ekspresijskih obrasca prijelazom u zreli oblik ECM-a; (3) otkriti korelate fetalnih ECM obrazaca na slikovnim prikazima MR u zdravlju (čovjek i štakor) i nakon blage do umjerene perinatalne hipoksije (štakor); (4) otkriti molekularni fenotip, staničnu i prostorno-vremensku distribuciju PNN u razvitku (čovjek i štakor) i promjene istih nakon perinatalne hipoksije u štakora te (5) korelirati ove promjene s bihevioralnim posljedicama hipoksije. Očekujemo da će istraživanje omogućiti da procijenimo značaj i ulogu molekula, obrazaca i reorganizacijskih procesa moždanog ECM-a. Rezultati projekta bit će nove znanstvene spoznaje, publikacije, unapređenje edukacije i pozicioniranje za daljnje međunarodne projekte usmjerene na razvoj novih istraživačkih, dijagnostičkih i terapijskih strategija za neurorazvojne poremećaje kao što su kognitivni deficiti, epilepsija, autizam ili shizofrenija.

Despite recent advances in the understanding of the importance of the neural extracellular matrix (ECM,  diffused or condensed as perineuronal nets, PNN) for physiological and pathological processes in the brain, it is still widely less recognized and researched than different neural cellular elements. To combat the lack of knowledge on key ECM players relevant for human brain development, basic researchers (at CIBR, Zagreb, and TU, Dresden) and clinically oriented researchers (at CHC Zagreb, AKH Vienna) will unite scientific approaches, models (human, rat, and organoids) and methodologies (3T and 7T magnetic resonance imaging (MRI), histological, molecular and behavioral), to address the following scientific aims: (1) to detect major differences in ECM constituents among the fetal brain zones, compartments, axonal strata, and cortical layers; (2) to disclose the different ECM expression patterns in the developing brain and (3) define the crucial time points of ECM expression patterns irreversible up-turns in transition to mature ECM form; (4) to reveal the correlates of the fetal ECM patterns in high-resolution MRI in health (human, rat) and after mild to moderate perinatal hypoxia in rat; (5) to disclose molecular phenotype, neuronal and spatial-temporal distribution of the PNN in health (human and rat) and their charges after perinatal hypoxia in rat and (6) to correlate the changes with behavioral consequences of the hypoxic lesion. These will enable us to evaluate the significance and the role of ECM constituents, and ECM reorganization, for the developmental processes (proliferation, migration, axon growth, folding, and synaptogenesis) in the human brain, in health and disorders. The outcome of the project will be new knowledge, publications, advances in education, and positioning for joint international proposals towards ECM-based research, diagnostic and therapeutic strategies, for neurodevelopmental disorders as cognitive disabilities, epilepsy, autism or schizophrenia

Bobić-Rasonja M, Pogledić, I, Mitter, C, Štajduhar, A, Milković-Periša, M, Trnski S, Bettelheim, D, Hainfellner, J,Judaš, M, Prayer, D, Jovanov-Milošević, N. Developmental differences between the limbic and neocortical telencephalic wall: an intrasubject slice-matched 3T MRI-histological correlative study in humans, Cer. Cortex, doi: 10.1093/cercor/bhab030, 2021

Milos, Ruxandra-Iulia; Jovanov-Milosevic, Natasa; Mitter, Christian; et al. Developmental dynamics of the periventricular parietal crossroads of growing cortical pathways in the fetal brain – In vivo fetal MRI with histological correlation. NEUROIMAGE, 116553; 210; 2020.  ‏

Vandervore, Laura V.; Schot, Rachel; Milanese, Chiara; et al.TMX2 Is a Crucial Regulator of Cellular Redox State, and Its Dysfunction Causes Severe Brain Developmental Abnormalities. AMERICAN JOURNAL OF HUMAN GENETICS, 105; 6:1126-1147; 2019.

Bobić Rasonja M, Orešković D, Knezović V, Pogledić I, Pupačić D, Vukšić M, Brugger P, Prayer D, Petanjek Z, Jovanov Milošević N. The Histological and MRI Study of the Development of the Human Indusium Griseum. CerCortex; DOI: 10.1093/cercor/bhz004 (Epub 2019 Feb 4).

Čuljat M and Jovanov Milošević N. Callosal septa express guidance cues and are paramedian guideposts for human corpus callosum development. JANAT (accepted 2018) DOI:10.1111/joa.13011.

Sedmak G, Jovanov Milošević N, Puskarjov M, Kaila K, Judaš M, Developmental Expression Patterns of KCC2 and Functionally Associated Molecules in the Human Brain. CerCortex.2016 Dec; 26(12) 4574-4589.

Jovanov Milošević N, Judaš M, Aronica E, Kostović I. Neural ECM in the laminar organization and connectivity development in the healthy and diseased human brain. Prog Brain Res.2014; 214:159-78.

Kostović I, Jovanov Milošević N, Radoš M, Sedmak G, Benjak V, Kostović-Srzentić M, Vasung L, Čuljat M, Radoš M, Hüppi P, Judaš M. Perinatal and early postnatal reorganization of the subplate and related cellular compartments in the human cerebral wall as revealed by histological and MRI approaches. Brain Struc Func 2014 Jan;219(1) 231-253.

Petanjek Z, Sedmak D, Dzaja D, Rasin RM, Jovanov Miloševic N. The Protracted Maturation of Associative Layer IIIC Pyramidal Neurons in the Human Prefrontal Cortex During Childhood: A Major Role in Cognitive Development and Selective Alteration in Autism. Front Psychiatry, 10:122.

Ilić K, Mlinac-Jerković K, Jovanov Milošević N, Šimić G, Habek N, Bogdanović N, Kalanj-Bognar S. Hippocampal expression of cell-adhesion glycoprotein neuroplastin is altered in Alzheimer’s disease. Journal of cellular and molecular medicine .J Cell Mol Med. 2019 Feb; 23(2):1602-1607.

Herrera-Molina R, Mlinac-Jerković K, Ilić K, Stober F, Vemula SK, Sandoval M, Jovanov Milošević N, Šimić G, Smalla KH, Goldschmidt J, Kalanj-Bognar S, Montaq G. Neuroplastin deletion in glutamatergic neurons impairs selective brain functions and calcium regulation: implication for cognitive deterioration. SCIENTIFIC REPORTS: 7 No7273, ( 2017)

Blažević SA, Šoltić D, Nikolić B, Ilić K, Jovanov Milošević N, Hranilović D. Perinatal Exposure of Rats to 5-Hydroxytryptophan Affects Midbrain Serotonin Homeostasis. Journal of Pharmacy and Pharmaceutical Research,2(2018), 1; 2, 8.

1. Bobić-RasonjaM, Pogledić I, Mitter C, Milković-Periša M, Hailfellner J, Judaš M, PrayerD, Jovanov-Milošević N. The interrelation of developmental zones’ thicknesses in mid-fetal human brain: a comparative MRI-histological study. FENS 2020 Virtual Forum, 7/2020.
2. Bobić-Rasonja M, Sedmak G, Knezović V, Radošević V, Jovanov-Milošević N. Transcriptome analysis of the human fetal anterior cingulate gyrus. Perinatal Origins of Neuropsychiatric Disorders: from molecular mechanisms to therapeutic perspectives. Palermo, Italy, 5/2019. https://www.bib.irb.hr/1006369
3. Bobić-Rasonja M, Štajduhar A, Sedmak G, Petrović D, Jovanov-Milošević N. Analysis of the MEF2C transcription factor expression in developing human cingulate gyrus. Hrvatski kongres neuroznanosti, Zadar, Croatia, 9/2019. https://www.bib.irb.hr/1071507
4. Orešković D, Sitaš B, Bobić M, Jovanov Milošević N. Expression of Perineuronal Nets in the Human Insula during Fetal and Perinatal Development. Controlling neuronal plasticity-developmental disorders and repair. Institute of Experimental Medicine CAS; Vila Lanna, Prague, Czechia; 12/2018.
5. Bobić M, Radošević V, Macan M, Jovanov Milošević N. ECM expression pattern in the human fetal cingulate gyrus and its relevance in malformations of cortical development. 1st Neuro-MIG Training School (EU Network on Brain Malformations, CA16118): Genomics and Imaging of Malformations of Brain Development, Zagreb, Croatia, 4/2018.
6. Bobić M, Knezović V, Sedmak G, Macan M, Radoš M, Vukšić M, Jovanov Milošević N. Immunohistochemical study of reorganizational processes in the human fetal cingulate gyrus. FENS Regional Meeting, Pečuh, Hungary, 9/2017.
7. Bobić M, Knezović V, Sedmak G, Macan M, Radoš M, Vukšić M, Jovanov Milošević N. Histochemical reorganizational processes in the human cingulate gyrus during midgestation. 6th Croatian Neuroscience Congress, Osijek, Croatia, 9/2017.
8. Trnski, S; Ilić, K; Nikolić, B; Darmopil, S; Petanjek, Z; Hranilović, D; Jovanov Milošević, N.: Lifelong changes in cingulate cortex and learning behavior after moderate perinatal hypoxia in the rat // FENS 2020 Virtual Forum, Glasgow, Škotska, 2020.
9. Barbara Nikolić, Sara Trnski, Kristina Košić, Dubravka Hranilović, Nataša Jovanov Milošević: Increased rearing and brainstem dopamine levels in a rat model of mild neonatal normobaric hypoxia // FENS 2020 – Virtual Forum, 11-15 July 2020, Virtualni forum (Glasgow, UK), 2020.
10. Trnski, Sara; Ilić, Katarina; Nikolić, Barbara; Habek, Nikola; Hranilović, Dubravka; Jovanov Milošević, Nataša: Changes of perineuronal nets morphology, hyperactive behavior and cognitive deficits in mild perinatal hypoxic brain lesion in rats; 7th Croatian Neuroscience Congress; Book of abstracts, str. 61-61; Zadar, Hrvatska; rujan, 2019;
11. Nikolić, Barbara; Trnski, Sara; Kološnjaj, Ivona; Stipan, Monika; Hranilović, Dubravka; Jovanov Milošević, Nataša: Effects of neonatal normobaric hypoxia on rat behavior at young and adult age; 7th Croatian Neuroscience Congress – Book of abstracts, str. 107-107; Zadar, Hrvatska; rujan, 2019.;
12. Putar, Darija; Zima, David; Trnski, Sara; Bobić Rasonja, Mihaela; Jovanov Milošević, Nataša: The Semaphorin5A developmental expression and functional role in mice telencephalon; 7th Croatian Neuroscience Congress; Book of abstracts, str. 88-88; Zadar, Hrvatska; rujan, 2019.;
13. Nikolić, Barbara; Trnski, Sara; Krizman, Matea; Jovanov Milošević, Nataša; Hranilović, Dubravka: Consequences of neonatal normobaric hypoxia on rat behaviour; FENS Regional Meeting – Connecting (Brain) Regions; Book of abstracts., str. 558-558; Beograd, Srbija, srpanj, 2019.;
14. Trnski, Sara; Ilić, Katarina; Nikolić, Barbara; Habek, Nikola; Hranilović, Dubravka; Jovanov Milošević, Nataša: Lifelong changes in perineuronal nets and the learning behavior in rats after mild perinatal hypoxic brain lesion; 7th Conference of the Mediterranean Neuroscience Society; Book of abstracts, str. 261-261; Marrakech, Maroko; lipanj, 2019.;
15. Trnski, Sara; Ilić, Katarina; Nikolić, Barbara; Habek, Nikola; Hranilović, Dubravka; Jovanov Milošević, Nataša: A non – invasive rat model of perinatal mild hypoxic brain damage; 14th FELASA Congress; Book of abstracts, str. 133-133; Prag, Češka, lipanj, 2019.;
16. Trnski, Sara; Ilić, Katarina; Nikolić, Barbara; Orešković, Darko; Habek, Nikola; Hranilović, Dubravka; Jovanov – Milošević, Nataša: The perinatal mild hypoxic brain lesion in rats causes changes in perineuronal nets morphology and impaired learning behavior; Controlling Neuronal Plasticity – developmental disorders and repair; Book of abstracts, str. 45-45; Prag, Češka; prosinac, 2018.;
17. Trnski, Sara; Ilić, Katarina; Nikolić, Barbara; Orešković, Darko; Habek, Nikola; Hranilović, Dubravka; Jovanov Milošević, Nataša: A new non – invasive model of perinatal mild hypoxic brain lesion causes lifelong changes of perineuronal nets and learning behavior in rats; Nikola Škreb Symposium: “New platforms in developmental biology – towards the clinical application”, Book of abstracts, str. 37-37; Zagreb, Hrvatska, studeni, 2018.;
18. Zima, David; Putar, Darija; Trnski, Sara; Bobić Rasonja, Mihaela; Jovanov Milošević, Nataša: The role of Semaphorin5A protein during brain development in rodents; Nikola Škreb Symposium: „New platforms in developmental biology towards the clinical application“; Book of abstracts, str. 38-38; Zagreb, Hrvatska; studeni, 2018.;
19. Putar, Darija; Zima, David; Trnski, Sara; Bobić Rasonja, Mihaela; Jovanov Milošević, Nataša: In vitro and in situ study of the role of Sema5A in the developing mouse telencephalon; Pokusne životinje u znanstvenim istraživanjima; Book of abstracts, str. 51-52; Zagreb, Hrvatska, listopad, 2018.;
20. Trnski, Sara; Ilić, Katarina; Nikolić, Barbara; Habek, Nikola; Hranilović, Dubravka; Jovanov Milošević, Nataša: A non-invasive rat model of perinatal hypoxic brain lesion; 3. znanstveno-stručni simpozij Hrvatskog društva za znanost o laboratorijskim životinjama i 2. zajednički skup CroLASA-e i SLAS-a s međunarodnim sudjelovanjem „Pokusne životinje u znanstvenim istraživanjima“; Book of abstracts, str. 47-48; Zagreb, Hrvatska, listopad, 2018.