En vävnad består av celler men en stor del av vävnadens volym är också extracellulärt utrymme som fylls ut av något som kallas bindväv. Bindväven består av olika proteiner och polysackarider som utsöndras av cellerna. Dessa proteiner sätts ihop till ett nätverk i nära kontakt med cellerna som producerar dem. Man kan säga att bindväven utgör byggnadsstommen i kroppen. Beroende på vilket organ och i vilket utvecklingsstadium organet befinner sig varierar andelen bindväv och dess proteinuppsättning. Förutom att bindväven stabiliserar vävnaden så har den en mycket aktiv och komplex roll, och reglerar cellernas uppträdande, påverkar cellernas utveckling, förflyttning, delning, form och funktion.
Basalmembran är en specialiserad typ av bindväv. Basalmembran är ett tunt nätverk som omger muskel-, fett-, och nervceller, men finns också under andra celltyper som epitel- och endotelceller. Basalmembranet kan även dela upp vävnaden i olika delar och fungerar då som en barriär eller som ett filter för cellerna. Även basalmembranen innehåller olika proteiner beroende på vävnadstyp och i vilket utvecklingsstadium de är. Basalmembran består i huvudsak av två proteinfamiljer, laminin och kollagen typ IV, och det är dessa proteiner som bildar det tunna nätverket. Jag har främst studerat lamininfamiljen, som består av 15 medlemmar numrerade 1-15. Varje laminin är uppbyggd av tre proteinkedjor en α-, en β- och en γ-kedja, och tillsammans bildar de ett större korsliknande protein. Förändringar i generna för dessa kedjor leder till olika muskeldystrofier och flera olika hudsjukdomar, cancer och troligen också till nervsjukdomar. Det har även visat sig att bakterier och virus kan använda basalmembranet som en länk för att infektera celler. När man har tagit bort generna för olika lamininkedjor i möss, man har gjort en så kallad knockout vilket innebär att genen som kodar för ett visst protein är borta och proteinet kan inte bildas längre, har det visat sig att nästan alla kedjorna är livsviktiga för att mössen ska kunna överleva. Saknar de en av kedjorna dör mössen oftast redan innan födseln.
I avhandlingens första del har jag bland annat studerat var laminin α 1-kedjan är uttryckt i fullvuxna möss. Det visade sig att den endast fanns på ett fåtal ställen i kroppen medan den i musfoster var något mer uttryckt. I tidigare
igen en annan lamininkedja, nämligen laminin α5-kedjan. Detta har gjort att man länge trodde att laminin α1-kedjan fanns i stort sett i alla basalmembran vilket vi nu visat att så är det inte. Laminin-1, som består av kedjorna α1, β1 och γ1, använder sig ofta av en mottagare eller receptor på cellen som kallas för dystroglycan. Vi har också studerats var dystroglycan finns i den vuxna muskroppen. Dystroglycan visade sig finnas i flera organ, i vissa organ fanns den tillsammans med laminin α1-kedjan och i andra organ tillsammans med α 2-kedjan. Dystroglycan verkar vara en mycket viktig receptor som binder cellerna till basalmembranet.
I andra delen har vi studerat hur celler i odling reagerar när de träffar olika sorters laminin. Vi kunde se att cellerna fäste sig olika bra till de olika lamininerna och att de fick olika utseenden beroende på vilken lamininsort de fäste sig till. Vidare har vi studerat vilka receptorer cellerna använde för att fästa sig till respektive laminin och vi upptäckte att de använde olika receptorer beroende på vilket laminin de satte sig på.
Sista delen i avhandlingen handlar om hur laminin kommunicerar med cellerna, dvs. vilka signaler laminin skickar till dem. Man har länge trott att bindväv eller basalmembran endast stabiliserar cellen men så är det inte.
Receptorerna på cellen kopplar nämligen ihop proteinerna på utsidan av cellen med proteinerna på insidan. Vi kunde se att flera lamininer startade cellsignaleringen via vissa av cellernas receptorer som i sin tur aktiverade proteiner inuti cellen. Gav vi dessutom cellerna tillväxtfaktorer (vitaminer och aminosyror är exempel på tillväxtfaktorer) så påverkade dessa tillsammans med laminin cellernas delning. Det gick också att stoppa signaleringen om man tillsatte kända blockerande ämnen.
Cellernas kommunikation med sin omgivning är förmodligen mycket mer komplex än vi kan tänka oss, men med en ökad förståelse för hur cellerna i kroppen fungerar och interagerar med sin omgivning kommer vi bättre kunna förstå sjukdomsmekanismer och förhoppningsvis då också finna nya botemedel.
ACKNOWLEDGEMENTS
This work has been carried out at “Zoofys” (later ICM) at Uppsala University and at the section of Cell and Developmental Biology at Lund University. I would like to express my warmest thanks to my co-authors and all present and past colleges for all the nice times in and outside the lab, thank you all!
In particular I would like to express my sincere gratitude to:
Peter Ekblom, my supervisor and mentor, for excellent guidance and support, and your scientific enthusiasm. You always manage to put everything into an interesting perspective.
Madde for help and guidance in the beginning and for introducing me to the lab.
Elke for your excellent guidance into the protein and signaling world, and for a nice friendship.
My roommates, Susanne and Mange, for making the Lund period as good as it became.
Good luck!
All the people at the lab in Lund; Marja, Maria, Tord, Hao, Yu Chen, Jan, Ulrika, Siw, Jang, and Alexander for nice collaborations and friendship.
The Cartela people and Emma for creating such a nice atmosphere, for pub evenings and parties.
The people from “zoofys”, which remained at Uppsala; Erik, Mats, Anne-Marie, Calle, Teet, Agnetha, Maria W., Olle and Sigrid. Special thanks to Maria R. and Katta, for
“taking care” of me during my “visits” at Uppsala University and to Donald for all the answers.
All my friends outside the lab, for reminding me of the world outside the lab and for all the fun things we have done together. No one mentioned, no one forgotten.
Robban for his patience, love and support during this time. Finally!
My parents and my brother Martin, for always believing in me, and for your endless support and love.
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