Sökning: id:"swepub:oai:DiVA.org:uu-7078" >
Anti-Diabetic and B...
Anti-Diabetic and Beta-Cell Protective Actions of Imatinib Mesylate
-
- Hägerkvist, Robert, 1976- (författare)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
-
Welsh, Nils (preses)
-
- Lernmark, Åke, Professor (opponent)
- University of Washington Departement of Medicine, Seattle
-
(creator_code:org_t)
- ISBN 915546615X
- Uppsala : Acta Universitatis Upsaliensis, 2006
- Engelska 58 s.
-
Serie: Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 1651-6206 ; 160
- Relaterad länk:
-
https://uu.diva-port... (primary) (Raw object)
-
visa fler...
-
https://uu.diva-port...
-
https://urn.kb.se/re...
-
visa färre...
Abstract
Ämnesord
Stäng
- Type 1 diabetes is a disease resulting from the progressive immune-mediated destruction of insulin producing β-cells. In order to understand more about diabetes we need to understand the mechanisms governing β-cell death.The leukemia drug Gleevec is a tyrosine kinase inhibitor that targets c-Abl. Surprisingly, Gleevec also counteracts Type 2 diabetes and acts as a cell death inhibiting agent, via inhibition c-Abl. Since both Type 1 and Type 2 diabetes are characterized by an increased β-cell death, and the role of c-Abl is unknown in β-cells, we wanted to investigate the following:1.Does Gleevec act via inhibition of c-Abl in β-cells?2.Can Gleevec treatment prevent beta-cell death and diabetes? 3.Which downstream signaling pathways are affected by Gleevec?In paper I, in order to determine whether Gleevec acts by inhibiting c-Abl, we used RNA-interference. Interestingly, siRNA against c-Abl produced by recombinant Dicer mediate almost complete and non-toxic silencing of c-Abl mRNA in dispersed islet cells and conferred protection from streptozotocin and cytokines.In paper II we show that Gleevec protects β-cells from nitric oxide, pro-inflammatory cytokines and streptozotocin in vitro and that Gleevec can prevent diabetes development in the NOD mouse and the streptozotocin-injected mouse. We also present the hypothesis that Gleevec induces a state resembling ischemic preconditioning.Paper III presents an additional mechanism by which Gleevec might improve β-cell survival, i.e. via the inhibition of the downstream stress-activated protein kinase c-Jun N-terminal kinase (JNK), the activity of which has been implicated in β-cell death signaling pathways. In paper IV we explore the interactions between the adaptor protein Shb and c-Abl. We presently show an association between Shb-c-Abl and that Shb is a substrate for the c-Abl kinase that might regulate stress-induced c-Abl activity.
Nyckelord
- Cell biology
- Cellbiologi
- Diabetes
Publikations- och innehållstyp
- vet (ämneskategori)
- dok (ämneskategori)
Hitta via bibliotek
Till lärosätets databas