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Pancreatic islet cells apoptosis: characterization and production of tools for the blockade of the stress signaling pathways

English title Pancreatic islet cells apoptosis: characterization and production of tools for the blockade of the stress signaling pathways
Applicant Bonny Christophe
Number 118193
Funding scheme Project funding
Research institution Unité de Génétique Moléculaire Falaises 1 - CHUV
Institution of higher education University of Lausanne - LA
Main discipline Endocrinology
Start/End 01.10.2007 - 30.09.2010
Approved amount 377'000.00
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Keywords (5)

type 1 diabetes; cytokines; signaling apoptosis; cell-penetrating peptides; rat and human islets

Lay Summary (English)

Lead
Lay summary
Type 1 diabetes is an autoimmune disease characterized by the progressive destruction of the pancreatic insulin-secreting cells (ß-cells) by apoptosis. During the development of the disease, apoptosis appears triggered by proinflammatory cytokines released by the activated macrophages and T-cells surrounding the inflamed islets. Both JNK and p38 MAPKs are major effectors controlling the apoptotic response of ß-cells. Pancreatic islet transplantation is a promising therapy to treat patients with type 1 diabetes. However a major restrictive problem with islet grafting is dependent upon poor islet recovery from donors. We have demonstrated that islet death during the isolation procedure recruits the JNK/p38 pathways. Therefore, influencing the activity of JNK/p38 represents an approach for affecting stress-induced signal transduction at a distal step in the signal cascade, potentially useful in future therapies aimed at reducing the destructive potential of ?-cell cytotoxic cytokines in type 1 diabetes and during the islets transplantation process. Insulin-secreting cells has the particularity to express the different JNK and p38 isoforms, i.e. JNK1,2,3 and p38?,?,?,?. As both JNKs and p38s are involved in controlling apoptosis as well as insulin secretion, it is of particular importance to assign to each isoform its particular role in apoptosis or insulin-secretion, if any. It will therefore be possible to block one function with limited interference on the other. In the present application, we propose to characterize the precise role of the JNK and p38 isoforms in ß-cells. Through RNA interference, gene silencing should be achieved with the use of synthetic, small interfering RNA (siRNA). By targeting these small, synthetic oligos against the specific JNK1,2,3 and p38?,?,?,? genes, we should identify their implication in insulin-secreting cell death and further develop new drugs to block the adequate isoforms.A way to inhibit JNK/p38 signal transduction is to prevent essential protein-protein interactions within signaling cascades. This might be efficiently performed by cell-penetrating peptides derived from small amino acids sequences mediating interaction between two protein partners. The JNK peptidic inhibitor (JNKi) was designed according to the JNK binding domain of IB1/JIP1. Indeed, blocking the JNK signaling pathway using JNKi leads to a high protection of ß-cells from cytokines-induced apoptosis ex vivo, and to a partial protection of isolated rat islets. Using the same approach as for JNKi, we propose to design new peptides against JNK and p38 isoforms. Preliminary results with peptides against p38?, p38? and JNK3 however failed to show any protection effect at reasonable peptide concentration (< 10 mM). Indeed, we recently showed that concentrations of cell permeable peptides above 10 mM are pro-apoptotic for insulin-secreting cells. We therefore have to improve the affinity of these peptides for their targets. This will be done by in silico modelisation in collaboration with O. Michielin (University of Lausanne) to finally try to block the JNKs/p38s pathways activated during the processes of human islet isolation and transplantation.
Direct link to Lay Summary Last update: 21.02.2013

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Associated projects

Number Title Start Funding scheme
105595 Development of cell-penetrating peptides to block stress signaling in human islets and improve transplantation for type 1 diabetic patients 01.10.2004 Project funding
133018 Pancreatic islet-cell apoptosis: characterization of JNK and p38 isoforms mediating b-cell failure 01.10.2010 Project funding
133018 Pancreatic islet-cell apoptosis: characterization of JNK and p38 isoforms mediating b-cell failure 01.10.2010 Project funding

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