Dataset Information

Platelet Proteomics to Understand the Pathophysiology of Immune Thrombocytopenia: Studies in Mouse Models

ABSTRACT: Immune thrombocytopenia (ITP) is an autoimmune disease characterized by enhanced platelet clearance and defective platelet production. Diagnosis by exclusion and “trial-error” treatment strategies are common practice, and despite the advancement conferred by Thrombopoietin receptor agonists (TPO-RA´s), many patients remain refractory. While the existence of different pathophysiological entities is acknowledged, we are still far from stratifying and understanding ITP, a necessary step in order to provide personalized treatment options. We propose that the platelet proteome may give diagnostic and prognostic insights into the disease. As a proof of principle, we aimed to dissect the potential platelet proteome dynamics in the so-called passive and active pre-clinical ITP mouse models. To do that, we obtained the platelet proteome at the thrombocytopenic stage and upon platelet count recovery (reached naturally or upon IVIg-treatment, depending on the model). While most of the proteomic alterations were common to both ITP models, there were model-specific protein dynamics. Interestingly, we observed that not all proteomic alterations were restored when the platelet count has returned to normal. We discuss the biological processes associated with the proteome dynamics observed. Our results show that profiling the platelet proteome may have great potential to improve the management of ITP in humans.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Blood Platelet, Platelet

SUBMITTER: Patricia Martínez-Botía

LAB HEAD: Laura Gutiérrez

PROVIDER: PXD028814 | Pride | 2022-08-12

REPOSITORIES: Pride

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Publications

Dissecting platelet proteomics to understand the pathophysiology of immune thrombocytopenia: studies in mouse models.

Martínez-Botía Patricia P Meinders Marjolein M De Cuyper Iris M IM Eble Johannes A JA Semple John W JW Gutiérrez Laura L

Blood advances 20220601 11

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by enhanced platelet clearance and defective platelet production. Diagnosis by exclusion and trial-and-error treatment strategies is common practice, and despite the advancement in treatment options, many patients remain refractory. Although the existence of different pathophysiological entities is acknowledged, we are still far from stratifying and understanding ITP. To investigate, we sought to dissect the platelet proteome d ...[more]

PMID: 35298626

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Project description:In sickle cell disease, ischemia-reperfusion injury and intravascular hemolysis produce endothelial dysfunction and vasculopathy characterized by reduced nitric oxide (NO) and arginine bioavailability. Recent functional studies of platelets in patients with sickle cell disease reveal a basally activated state, suggesting that pathological platelet activation may contribute to sickle cell disease vasculopathy. Studies were therefore undertaken to examine transcriptional signaling pathways in platelets that may be dysregulated in sickle cell disease. We demonstrate and validate here the feasibility of comparative platelet transcriptome studies on clinical samples from single donors, by the application of RNA amplification followed by microarray-based analysis of 54,000 probe sets. Data mining an existing microarray database, we identified 220 highly abundant genes in platelets and a subset of 72 relatively platelet-specific genes, defined by more than 10-fold increased expression compared to the median of other cell types in the database with amplified transcripts. The highly abundant platelet transcripts found in the current study included 82% or 70% of platelet abundant genes identified in two previous gene expression studies on non-amplified mRNA from pooled or apheresis samples, respectively. On comparing the platelet gene expression profiles in 18 patients with sickle cell disease in steady state to 12 African American controls, at a 3-fold cut-off and 5% false discovery rate, we identified ~100 differentially expressed genes, including multiple genes involved in arginine metabolism and redox homeostasis. Further characterization of these pathways using real time PCR and biochemical assays revealed increased arginase II expression and activity and decreased platelet polyamine levels. These studies suggest a potential pathogenic role for platelet arginase and altered arginine and polyamine metabolism in sickle cell disease and provide a novel framework for the study of disease-specific platelet biology. Experiment Overall Design: There are 18 sickle cell samples and 12 control samples from healthy African American volunteers.

Dataset Information

Platelet Proteomics to Understand the Pathophysiology of Immune Thrombocytopenia: Studies in Mouse Models

Publications

Dissecting platelet proteomics to understand the pathophysiology of immune thrombocytopenia: studies in mouse models.

Similar Datasets

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