20.500.12556/RUL-99016 Identification of signaling pathways controlling survival of pancreatic beta-cells in diabetes Identifikacija signalnih poti za uravnavanje preživetja beta-celic trebušne slinavke pri sladkorni bolezni 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. 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. PHLPP1 2/mTOR YAP Hippo pathway MST1 beta-cells pancreas diabetes PHLPP1 2/mTOR YAP Hippo signalna pot MST1 beta-celice trebušna slinavka sladkorna bolezen true false false [B. Lupše] Slovenski jezik Angleški jezik Magistrsko delo/naloga 2017-12-21 07:15:35 2017-12-21 07:15:45 2022-08-16 10:27:54 0000-00-00 00:00:00 2017 0 0 Univerzitetna Prešernova nagrada / University Prešern Award 2018 0000-00-00 NiDoloceno NiDoloceno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 606:616.379-008.64:591437:577.151(043.2) 150608 8908665 1649.pdf 1649.pdf 1 7E03ED24768856C1F27A7BC425D7830D f50965d8c09b71b3ca3d256dbeff1d2d6a2a2f53f86997a3b795b8e71d2055ec 79ec5e17-a1b4-11eb-a523-00155dcfd717 20.500.12556/rul/b8f73e79-24b9-49ad-96f5-123cac4f2021 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=108359 Biotehniška fakulteta 0 0 0