Schmugge
Fakultäten » Medizinische Fakultät » Kinderspital Zürich: Medizinische Klinik » Hämatologie, Abteilung » PD Dr. Markus Schmugge Liner » Schmugge
Current research project
| Title / Titel | Platelet apoptosis in the course of childhood immune-thrombocytopenia | ||||||||
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| Abstract (PDF, 14 KB) | |||||||||
| Summary / Zusammenfassung | Childhood immune-thrombocytopenic purpura is a well-known disorder with autoimmune processes leading to destruction of platelets. In most of the cases bleeding symptoms are minor and the disease resolves spontaneously after weeks to months. Nevertheless, in about 20% of patients the disease lasts more than 6 to 12 months taking a chronic course. In literature the percentage of severe and even fatal haemorrhage varies around 1% and is associated with platelet counts <10 x 109/l. Treatment with IVIg or steroids leads to increased platelet counts. The mechanism of action of this therapy in ITP is not fully understood. For IVIg, besides blockage of the reticuloendothelial system via Fc-receptors, there are different mechanisms discussed, including the interference with apoptotic processes in platelets. Data from mouse models strongly suggest that a tight control of the protein degradation of the anti-apoptotic Bcl-XL serves as a molecular clock to regulate platelet lifespan. Indeed, Bcl-XL controls the pro-death activity of pro-apoptotic Bak in platelets. Decreasing levels of Bcl-XL over time leads to platelet destruction (Mason et al. Cell 2007). Other anti-apoptotic regulators do not appear to be involved in this mechanism, at least in mouse. Thus the balance between anti-apoptotic Bcl-XL and pro-apoptotic Bak appears to play a central role in regulating platelet survival. It is therefore possible that abnormal signals that are triggered during the active phase of ITP may directly affect the molecular clock regulating platelet life span and contribute to the destructive process. In a prospectively study we evaluated laboratory parameters that reflect immune activation, platelet activation and caspase activation in platelets by comparing a series of 12 patients with newly diagnosed ITP to healthy controls. Our data indicate that activation of a caspase dependent cell death pathway in platelets is associated with the active phase of childhood ITP. Strikingly, caspase activation decreases to levels that are detected in normal controls when children respond to IVIG treatment, which is consistent with observations described in a murine model of ITP (Leytin et al. BJH 2006). We now plan to specify our investigations by identifying proteins and factors involved in the signaling pathway leading to programmed cell death in platelets. In the proposed project, we will elucidate the role of programmed cell death of platelets in childhood ITP. We will investigate the signaling pathway of apoptosis in platelets of patients with ITP during the course of the disease. Specifically we will define proteins relevant in programmed cell death of platelets and therefore relevant for normal platelet homeostasis. The next step will be to study their role in immune thrombocytopenia: at initial presentation and in the course of the disease, where also the effect of treatment with IVIg and/or steroids will be looked at. The study setting allows generating laboratory data in ITP patients, to correlate them to the clinical course of the patients and to compare them to healthy controls. With the proposed project we aim to get deeper knowledge of apoptotic changes in platelets in healthy humans, as well as in disease, in which the platelet homeostasis is altered. This will lead to a better understanding of the pathomechanisms of ITP. The new insights might reveal new therapeutic targets and might even lead to the development of new drugs for the treatment of chronic ITP. The correlation of clinical data and bleeding-scores to laboratory findings will finally help us to better answer the major therapeutic question: whom to treat or not to treat in ITP. Weitere Informationen |
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| Project leadership and contacts / Projektleitung und Kontakte |
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| Funding source(s) / Unterstützt durch |
Foundation, No project-specific funding Theodor und Ida Herzog-Egli Stiftung |
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| Duration of Project / Projektdauer | May 2009 to Apr 2012 |