RAZPIS ZA MLADEGA RAZISKOVALCA (m/ž)

V programski skupini Proteoliza in njena regulacija pri zdravju in boleznih (vodja: prof. ddr. Turk Boris) vabimo zainteresirane kandidate na prijavo na razpis za mladega raziskovalca*. Mentor mlademu raziskovalcu bo dr. Robert Vidmar, raziskovalno delo bo potekalo na Odseku za biokemijo, molekularno in strukturno biologijo, na Inštitutu Jožef Stefan. Na prijavo na razpis vabljeni kandidati, ki bodo do 14. septembra 2022 zaključili magistrski študij na 2. stopnji naravoslovnih smeri, kot so biokemija, kemija, farmacija, mikrobiologija, laboratorijska medicina oz. primerljive študijske smeri.  

Kandidati vabljeni, da na spletni strani Instituta »Jožef Stefan« do 31. julija 2022 oddajo prijavo za mesto mladega raziskovalca. Kandidati bodo vabljeni na informativne razgovore z mentorjem, ki bodo potekali v mesecih julij in avgust oz. do zapolnitve delovnega mesta. Začetek raziskovalnega dela je predviden v jeseni 2022.       

Kratek opis raziskovalnega dela:

Tema raziskovalnega dela mladega raziskovalca bo identifikacija biomarkerjev in molekularnega mehanizma pri normotenzivnem hidrocefalusu. Za normotenzivni hidrocefalus neznanega izvora (iNTH) je značilno nenormalno kopičenje cerebrospinalne tekočine (CSF) v možganskih ventriklih. Vzrok motnje ni znan in se pojavlja pri ljudeh vseh starosti, pogostejši pa je pri starejših. Znaki in simptomi, za katere je ugotovljeno, da so povezani z iNTH, so motnje hoje, demenca in urinska inkontinenca. Ker so omenjeni simptomi pogosti pri starejših osebah in imajo veliko vzrokov, je iNTH težko diagnosticirati. Poleg tega so simptomi pri iNTH podobni tistim pri drugih nevroloških motnjah, kot so Alzheimerjeva bolezen (AD), Parkinsonova bolezen in Creutzfeldt-Jakobova bolezen. Zaradi teh vzrokov je iNTH pogosto napačno diagnosticiran in zato veliko primerov ostane neprepoznanih in posledično ne pride do pravilnega zdravljenja. Čeprav obstaja več molekularnih biomarkerjev za podobne motnje, zlasti AD (amiloid-β, skupni tau in fosforiliran tau), diagnoza iNTH nima molekularne osnove za natančno identifikacijo uporabno v kliničnem okolju.

Ker je diagnoza iNTH pogosto zahtevna in nagnjena k pozni oz. napačni diagnozi, je cilj tega raziskovalnega projekta identificirati biomarkerje iNTH. S poznavanjem vsebine cerebrospinalne tekočine na molekularnem nivoju in diagnoz pacientov si želimo poleg identifikacije novih biomarkerjev za iNTH raziskati in osvetliti  molekularne mehanizme povezane z nastankom iNTH za izbiro optimalne strategije zdravljenja in zmanjšanje simptomov pri prizadetih bolnikih.

Raziskovalna področja kandidata bodo vsebovala proteomsko analizo CSF z visoko zmogljivo masno spektrometrijo za identifikacijo in relativno kvantificiranje vsebnosti proteinov. Nadalje bodo tarče, identificirane kot potencialni biomarkerji, potrjene s komplementarnimi pristopi. Glavni pristop validacije bo imunološko odkrivanje tarčnih proteinov, s primarnim ciljem potrditi korelacijo s podatki z MS. Za zagotovitev absolutnih vrednosti tarčnih proteinov bomo izvedli ELISA za visoko selektivne tarče in vzpostavili teste biomarkerjev iNTH. Ker preliminarni rezultati kažejo na potencialno povezavo med diferencialnim sproščanjem zunajceličnih domen ciljnih proteinov, si bomo prizadevali ugotoviti izvor tega procesa in oceniti proteolitično aktivnost v CSF. Cilj raziskave je torej identifikacija novih biomarkerjev za iNTH in osvetliti mehanizem nastanka te bolezni, zmanjšati delež napačnih diagnoz iNTH ter olajšati izbiro učinkovitega zdravljenja.

Dodatne informacije: dr. Robert Vidmar, robert.vidmar@ijs.si oz. na spletni strani odseka.

*V razpisu uporabljeni izrazi, zapisani v slovnični obliki moškega spola, so uporabljeni kot nevtralni in veljajo enakovredno za oba spola.

FEBS ICGEB workshop ‘Proteolysis: at the interface between health and disease

Dear colleagues and friends,


it is our pleasure to invite you to this year’s  FEBS ICGEB workshop ‘Proteolysis: at the interface between health and disease’.

This workshop aims at addressing current issues, progress, and expansion taking place in the field of proteases, protein inhibitors and their mechanisms of control under physiological and pathological conditions. Several sections will be devoted to proteases, protease inhibitors, regulation and proteolytic control with emphasis on their role in diseases, as well as on novel therapeutic approaches, and in vivo imaging and diagnostic strategies, which tackle protease activities. Additionally, several sections will be devoted to tutoring and mentoring activities, which are crucial for the information and knowledge exchange among senior scientists and early career researchers.

We are looking forward to seeing you in the enchanting environment of Bled in September!

Boris Turk,
Chair of the organizing committee

Article in Cells: Cystatin C Deficiency Increases LPS-Induced Sepsis and NLRP3 Inflammasome Activation in Mice

In collaboration with the colleagues from the Faculty of Medicine and Faculty of Chemistry and Chemical Technology, University of Ljubljana, we published a paper entitled: Cystatin C Deficiency Increases LPS-Induced Sepsis and NLRP3 Inflammasome Activation in Mice (Cells2021, 10(8), 2071; https://doi.org/10.3390/cells10082071)

Abstract

Cystatin C is a potent cysteine protease inhibitor that plays an important role in various biological processes including cancer, cardiovascular diseases and neurodegenerative diseases. However, the role of CstC in inflammation is still unclear. In this study we demonstrated that cystatin C-deficient mice were significantly more sensitive to the lethal LPS-induced sepsis. We further showed increased caspase-11 gene expression and enhanced processing of pro-inflammatory cytokines IL-1β and IL-18 in CstC KO bone marrow-derived macrophages (BMDM) upon LPS and ATP stimulation. Pre-treatment of BMDMs with the cysteine cathepsin inhibitor E-64d did not reverse the effect of CstC deficiency on IL-1β processing and secretion, suggesting that the increased cysteine cathepsin activity determined in CstC KO BMDMs is not essential for NLRP3 inflammasome activation. The CstC deficiency had no effect on (mitochondrial) reactive oxygen species (ROS) generation, the MAPK signaling pathway or the secretion of anti-inflammatory cytokine IL-10. However, CstC-deficient BMDMs showed dysfunctional autophagy, as autophagy induction via mTOR and AMPK signaling pathways was suppressed and accumulation of SQSTM1/p62 indicated a reduced autophagic flux. Collectively, our study demonstrates that the excessive inflammatory response to the LPS-induced sepsis in CstC KO mice is dependent on increased caspase-11 expression and impaired autophagy, but is not associated with increased cysteine cathepsin activity.