M. Sc. thesis
Povzetek
B Both, type 1 (T1D) and type 2 (T2D) diabetes mellitus involve the loss of functional insulin-producing beta-cell mass, where autoimmunity in T1D and apoptotic signalling in T2D are main causes for beta-cell death but their underlying mechanisms are poorly understood. In this thesis, we have investigated several interconnected signaling pathways controlling pancreatic beta-cell function and survival in diabetes. We have found that: (I) small molecule inhibitor of Hippo kinase MST1 improved beta-cell survival in human islets and in an established beta-cell line in vitro. (II) Islet-overexpression of the Hippo terminal effector YAP protects beta-cells from apoptosis triggered by multiple diabetogenic conditions. (III) mTORC1 signaling is activated in isolated islets from diabetic mouse models and its genetic and pharmacological suppression improved beta-cell function. (IV) PHLPP 1 and 2 phosphatases promote beta-cell dysfunction and death, and are regulated by mTORC1 signaling under diabetic conditions in beta-cells. These analyses confirm the importance of Hippo pathway components (MST1 and YAP) for the regulation of β-cell survival in diabetes. Also, mTORC1 has been identified as novel regulator of the PHLPP-MST1 signaling axis, which is highly activated under a diabetic milieu, suggesting a novel Hippo-dependent cellular program, regulated by PHLPP and mTOR1 signaling, which balances beta-cell homeostasis.
Ključne besede
PHLPP 1/2;mTOR;YAP;Hippo pathaway;MST1;beta cells;pancreas;diabetes;
Podatki
Jezik: |
Angleški jezik |
Leto izida: |
2017 |
Tipologija: |
2.09 - Magistrsko delo |
Organizacija: |
UL BF - Biotehniška fakulteta |
Založnik: |
[B. Lupše] |
UDK: |
606:616.379-008.64:591437:577.151(043.2) |
COBISS: |
8908665
|
Št. ogledov: |
1533 |
Št. prenosov: |
487 |
Ocena: |
0 (0 glasov) |
Metapodatki: |
|
Ostali podatki
Sekundarni jezik: |
Slovenski jezik |
Sekundarni naslov: |
Identifikacija signalnih poti za uravnavanje preživetja [beta]-celic trebušne slinavke pri sladkorni bolezni |
Sekundarni povzetek: |
I Oba tipa sladkorne bolezni, sladkorna bolezen tipa 1 (SBT1) in tipa 2 (SBT2), sta povezani z izgubo funkcionalne mase beta-celic, ki proizvajajo inzulin. Avtoimunost pri SBT1 in apoptotično signaliziranje pri SBT2 sta glavna vzroka za smrt teh celic, a so osnovni mehanizmi za to slabo poznani. V tem magistrskem delu smo preučevali več medsebojno povezanih signalnih poti, ki nadzorujejo funkcijo beta-celic in njihovo preživetje pri sladkorni bolezni. Ugotovili smo, da: (I) inhibitor Hippo kinaze MST1 izboljša preživetje in delovanje beta-celic v človeški trebušni slinavki in uveljavljeni beta-celični liniji in vitro. (II) povečana ekspresija Hippo terminalnega efektorja YAP ščiti beta-celice pred apoptozo, ki jo sprožijo razmere pri diabetesu. (III) signaliziranje mTORC1 je prekomerno aktivirano v trebušni slinavki diabetičnih miši, njegova genetska in farmakološka inaktivacija pa izboljša funkcijo β-celic. (IV) PHLPP 1 in 2 fosfataze povzročajo zmanjšano funkcijo β-celic in njihovo smrt v diabetičnih razmerah in so pozitivno regulirane preko mTORC1. Te analize potrjujejo pomembnost Hippo signalne poti (MST1 in YAP) za uravnavanje preživetja β-celic pri sladkorni bolezni. Tudi mTORC1 je bil identificiran kot nov regulator PHLPP-MST1 signalne osi, ki je močno aktivirana v diabetičnih razmerah, kar kaže na novo regulacijo Hippo poti regulirane preko PHLPP in mTOR1 signaliziranja, ki uravnava beta-celično homeostazo. |
Sekundarne ključne besede: |
PHLPP1/2;mTOR;YAP;Hippo signalna pot;MST1;beta celice;trebušna slinavka;sladkorna bolezen; |
Vrsta dela (COBISS): |
Magistrsko delo/naloga |
Študijski program: |
0 |
Komentar na gradivo: |
Univ. v Ljubljani, Biotehniška fak., Študij biotehnologije |
Komentar vira: |
Univerzitetna Prešernova nagrada / University Prešern Award 2018 |
Strani: |
X, 68 f. |
ID: |
10915144 |