Unravelling the role of ROCK in the pathological retina

Lien Veys
Het ontrafelen van de rol van het ROCK molecule in neurodegeneratieve ziekten zoals glaucoom,

‘ROCK inhibitie’ klinkt glaucoompatiënten als muziek in de oren

Ooit al gehoord van de term ‘neurodegeneratieve ziekten’? Misschien wel, misschien ook niet. In elk geval zal één van de volgende neurodegeneratieve ziekten je wel bekend in de oren klinken; de ziekte van Parkinson, frontotemporale dementie, amyotrofe laterale sclerose (ALS), de ziekte van Alzheimer, glaucoom of de ziekte van Huntington, zijn allemaal ziekten van het zenuwstelsel waarbij in de loop der jaren zenuwcellen afsterven.

In het kader van haar biologieopleiding onderzocht Lien Veys voor haar masterthesis wat de rol is van ROCK moleculen bij neurodegeneratieve ziekten zoals bv. glaucoom.

Het oog als modelsysteem

Omdat neurodegeneratieve ziekten vaker optreden bij ouderen, stijgt het aantal mensen dat hieraan lijdt in onze vergrijzende samenleving. Dergelijke ziekten verminderen de levenskwaliteit van de patiënten aanzienlijk en zijn bovendien nog niet te genezen of zelfs af te remmen. In sommige gevallen kan de vooruitgang van de ziekte wat vertraagd worden, maar eenmaal een zenuwcel in het centraal zenuwstelsel (waar ook de hersenen deel van uitmaken) beschadigd is, kan deze niet meer teruggroeien en is er geen of slechts een onvolledig herstel mogelijk. Daarom is het hoogstnodig nieuwe strategieën te ontwikkelen, die gericht zijn op het behoud van de beschadigde zenuwcellen en het herstel ervan.

Aangezien het oog informatie doorgeeft aan de hersenen via zenuwcellen in het netvlies, kan eveneens in dit circuit neurodegeneratie optreden. Verder is het netvlies structureel en functioneel zeer gelijkaardig aan de rest van de hersenen. Bovendien is het optische circuit anatomisch eenvoudig, gemakkelijk te manipuleren en bereikbaar via het oog, wat het een ideaal modelsysteem maakt om neurodegeneratieve ziekten te bestuderen. Zo kunnen we door het oog te bestuderen niet enkel informatie vergaren over neurodegeneratieve oogziekten, zoals glaucoom, maar ook over andere neurodegeneratieve ziekten in de hersenen.

ROCK inhibitie als strategie voor het beschermen en herstellen van zenuwcellen

Recent is de inhibitie van het Rho-associated coiled-coil kinase (ROCK) molecule naar voor geschoven als een efficiënte en veelbelovende strategie voor het beschermen en herstellen van zenuwcellen. Omdat de exacte werkingsmechanismen van ROCK nog niet gekend zijn, was het doel van dit onderzoek om de rol van ROCK gedetailleerder te ontrafelen. Hierbij werd niet enkel gekeken hoe ROCK werkt in gezonde cellen en weefsels, maar ook in een ziek oog. ROCK kan tevens onder 2 vormen voorkomen en wordt dan ROCK1 of ROCK2 genoemd. In welke cellen en weefsels meer of minder ROCK1 of ROCK2 aanwezig is en of veranderingen in dit patroon verschillen tussen beiden vormen is echter nog niet volledig opgehelderd.

ROCK onderzocht op 2 niveaus

Om menselijke ziekten te bestuderen worden vaak levende proefdieren gebruikt die model staan voor de mens, dit heet in vivo onderzoek en heeft over de jaren heen al veel succes opgeleverd. Het is echter niet altijd even eenvoudig om een menselijke ziekte na te bootsen in een ander dier. Het lichaam is zo complex dat het vaak moeilijk is om de verschillende factoren te onderscheiden die een rol spelen bij de balans van het lichaam. Bovendien is het houden van dieren voor laboratoriumonderzoek vaak een kostelijke en tijdrovende aangelegenheid. Om experimenten eenduidiger, sneller en efficiënter te laten verlopen en minder proefdieren te gebruiken is er een hele batterij nieuwe technieken beschikbaar om basisonderzoek te doen, zoals in vitro en ex vivo methodes, beiden gebruikt in deze thesis.

In vitro

De in vitro aanpak is steeds populairder; hierbij worden cellen uit het lichaam gehaald, van elkaar los gemaakt en in een kamertje gehouden dat de omstandigheden van het lichaam nabootst, wat ‘cellen in cultuur brengen’ heet. Op die manier kunnen grote hoeveelheden cellen aan een relatief lage prijs in cultuur worden gehouden en het kan effect van bepaalde veranderingen hierin eenduidig bestudeerd worden in een gecontroleerde omgeving. Aangezien het exacte ROCK1 en ROCK2 patroon ook in het netvlies nog niet volledig gekarakteriseerd is, werden eerst de ROCK1 en ROCK2 levels bestudeerd in gezonde en zieke retinale cellen, geïsoleerd uit varkensogen. Varkens werden gebruikt omdat cellen in varkensogen talrijk, groot en gemakkelijk in cultuur te houden zijn. Daarenboven waren de varkensogen slachtafval van een slachthuis en hoefden er geen echte proefdieren gebruikt te worden. Om een neurodegeneratieve omgeving na te bootsen, werden de cellen ziek gemaakt door een stressor toe te voegen, die ook aanwezig is in de neurodegeneratieve retina. Deze experimenten toonden een duidelijke aanwezigheid van ROCK in bepaalde gezonde cellen in het netvlies aan en legden differentiële veranderingen in ROCK1 en ROCK2 levels in zieke cellen bloot.

Ex vivo

Bij het gebruik van in vitro modellen wordt er echter geen rekening gehouden met de interacties tussen de cellen in een weefsel. Daarom werd ook de ex vivo aanpak gebruikt, waarbij een deeltje van een weefsel in cultuur wordt gebracht. In dit onderzoek werd zowel weefsel van het netvlies van varkens als van muizen gebruikt. Deze weefseldeeltjes, ook explanten genoemd, zijn vaak een ideale manier om het effect van nieuwe therapeutische moleculen te onderzoeken. Voor deze thesis werd een varkensexplant modelsysteem gekarakteriseerd dat een neurodegeneratieve retina nabootst. Dit model zou dan in de toekomst gebruikt kunnen worden om geneesmiddelen (bvb. ROCK1 of/en ROCK2 inhibitoren) op grote schaal te testen en om te onderzoeken of ze de neurodegeneratieve retina al dan niet kunnen herstellen. Tot slot werden de effecten van ROCK inhibitors getest op explanten van heel jonge muizen waarvan de zenuwcellen nog heel goed kunnen groeien. Deze ROCK inhibitors bleken wel degelijk een positief effect te hebben op de initiële fase van het teruggroeien van de connecties van de zenuwcel.

Een stapsteen naar nieuwe therapieën

Globaal gezien legde dit onderzoek al een aantal belangrijke aspecten van het werkingsmechanisme van ROCK bloot, werd ROCK gedetailleerder gelokaliseerd en opgevolgd en werd er een neurodegeneratief model gevalideerd dat gebruikt kan worden om de kracht van nieuwe ROCK inhibitoren te testen. Bovendien werd het positief effect van ROCK inhibitie in neurodegeneratie aangestipt. Deze studie benadrukte ook de nood aan het verder ontrafelen van ROCK in neurodegeneratieve processen, om ROCK inhibitie te kunnen gebruiken als een innovatieve therapie voor neurodegeneratieve (oog)ziekten, zoals glaucoom.

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Universiteit of Hogeschool
Biologie
Publicatiejaar
2016
Promotor(en)
Lieve Moons
Kernwoorden
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