M. Sc. thesis
Blaž Lupše (Author), Marko Kreft (Mentor), Marko Kreft (Thesis defence commission member), Kathrin Maedler (Thesis defence commission member), Mojca Narat (Thesis defence commission member), Tadej Battelino (Thesis defence commission member), Kathrin Maedler (Co-mentor)

Abstract

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.

Keywords

PHLPP 1/2;mTOR;YAP;Hippo pathaway;MST1;beta cells;pancreas;diabetes;

Data

Language: English
Year of publishing:
Typology: 2.09 - Master's Thesis
Organization: UL BF - Biotechnical Faculty
Publisher: [B. Lupše]
UDC: 606:616.379-008.64:591437:577.151(043.2)
COBISS: 8908665 Link will open in a new window
Views: 1533
Downloads: 487
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Other data

Secondary language: Slovenian
Secondary title: Identifikacija signalnih poti za uravnavanje preživetja [beta]-celic trebušne slinavke pri sladkorni bolezni
Secondary abstract: 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.
Secondary keywords: PHLPP1/2;mTOR;YAP;Hippo signalna pot;MST1;beta celice;trebušna slinavka;sladkorna bolezen;
Type (COBISS): Master's thesis/paper
Study programme: 0
Thesis comment: Univ. v Ljubljani, Biotehniška fak., Študij biotehnologije
Source comment: Univerzitetna Prešernova nagrada / University Prešern Award 2018
Pages: X, 68 f.
ID: 10915144