Regulation of neutrophil and platelet function by miR-146a in NETosis; consequences on thrombogenesis and therapeutic potential (Q3157119): Difference between revisions
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(Created claim: summary (P836): Mir-146a, a miRNA expressed mostly in inflammatory cells, could play an active role in the development of atherothrombotic processes. The objectives of this project are (i) to determine the role of miR-146a in the NETosis process and how rs2431697, miR-SNP present in the gene that encodes this miRNA and which reduces its levels, can influence the development of thrombosis in patients with pro-thrombotic pathology, (ii) investigate the contributi...) |
(Changed label, description and/or aliases in en: translated_label) |
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Regulation of neutrophil and platelet function by miR-146a in NETosis; consequences on thrombogenesis and therapeutic potential | |||
Revision as of 15:19, 12 October 2021
Project Q3157119 in Spain
| Language | Label | Description | Also known as |
|---|---|---|---|
| English | Regulation of neutrophil and platelet function by miR-146a in NETosis; consequences on thrombogenesis and therapeutic potential |
Project Q3157119 in Spain |
Statements
89,600.0 Euro
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112,000.0 Euro
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80.0 percent
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1 January 2018
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31 March 2021
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FUNDACION PARA LA FORMACION E INVESTIGACION SANITARIAS DE LA REGION DE MURCIA (FFIS)
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37°59'32.57"N, 1°7'49.94"W
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30030
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Mir-146a, un miRNA expresado mayoritariamente en células inflamatorias, podría jugar un papel activo en el desarrollo de procesos aterotrombóticos. Los objetivos de este proyecto son (i) determinar el papel de miR-146a en el proceso de NETosis y cómo rs2431697, miR-SNP presente en el gen que codifica este miRNA y que reduce sus niveles, puede influir en el desarrollo de trombosis en pacientes con patologia pro-trombótica, (ii) investigar la contribución de miR-146a plaquetario como nexo entre NETosis y trombosis y finalmente (iii) evaluar la potencial acción terapéutica de miR-146a en aterotrombosis. Para ello, analizaremos el efecto de la deficiencia de mir-146a en la capacidad intrínseca de los neutrófilos para formar NET empleando un modelo murino deficiente para este miRNA y también un modelo celular humano deficiente en miR-146a generado por CRISPR-cas9. Valoraremos diferentes marcadores de NETosis (DNA, histona 3 citrulinada) tras activación de neutrófilos purificados con PMA. Estudiaremos el impacto de rs2431697 en la formación de NET en neutrófilos de pacientes con fibrilación auricular y pacientes con artritis reumatoide. Realizaremos estudios de asociación entre marcadores plasmáticos de NETosis (DNA, elastasa, mieloperoxidasa, ROS) y la presencia de rs2431697 en el desarrollo de eventos trombóticos en estas cohortes. Valoraremos la función plaquetaria en ratones deficientes en miR-146a y el impacto en la formación de NET in vivo en ratones miR-146a-/- y en pacientes. Investigaremos nuevas dianas de miR-146a en plaquetas y neutrófilos implicadas en la formación de NET por RNA-seq comparando la expresión de transcritos de muestras de ratones miR-146a-/- vs. WT. Finalmente, estudiaremos el efecto de la sobreexpresión sistémica de miR-146a en dos modelos de ratones: (i) modelo de aterosclerosis donde estudiaremos regresión de la placa tras 16 semanas de dieta grasa y (ii) reducción de la trombosis arterial en modelo trombosis carotídea inducida por FeCl3d (Spanish)
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Mir-146a, a miRNA expressed mostly in inflammatory cells, could play an active role in the development of atherothrombotic processes. The objectives of this project are (i) to determine the role of miR-146a in the NETosis process and how rs2431697, miR-SNP present in the gene that encodes this miRNA and which reduces its levels, can influence the development of thrombosis in patients with pro-thrombotic pathology, (ii) investigate the contribution of miR-146a platelet as a nexus between NETosis and thrombosis and finally evaluate the potential therapeutic action of miR-146a in atherothrombosis. To do this, we will analyse the effect of mir-146a deficiency on the intrinsic capacity of neutrophils to form NET using a deficient murine model for this miRNA and also a human cell model deficient in miR-146a generated by CRISPR-cas9. We will evaluate different markers of NETosis (DNA, histone 3 cytrulinated) after activation of neutrophils purified with PMA. We will study the impact of rs2431697 on the formation of NET in neutrophils in patients with atrial fibrillation and patients with rheumatoid arthritis. We will conduct association studies between plasma markers of NETosis (DNA, elastase, myeloperoxidase, ROS) and the presence of rs2431697 in the development of thrombotic events in these cohorts. We will assess platelet function in miR-146a deficient mice and the impact on in vivo NET formation in miR-146a-/- mice and in patients. We will investigate new miR-146a targets in platelets and neutrophils involved in the formation of NET by RNA-seq by comparing the expression of transcripts from miR-146a-/- vs. WT mice samples. Finally, we will study the effect of systemic overexpression of miR-146a on two models of mice: (I) atherosclerosis model where we will study plaque regression after 16 weeks of fat diet and (ii) reduction of arterial thrombosis in FeCl3d-induced carotid thrombosis model (English)
12 October 2021
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Murcia
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Identifiers
PI17_00051
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