Descripción del proyecto
El papel de los neutrófilos en la eliminación de residuos de ADN necrótico
El cuerpo humano pierde cada día miles de células debido al proceso de muerte celular conocido como necrosis. La eliminación inadecuada de los residuos celulares, como el ADN, se vincula con afecciones como el lupus eritematoso sistémico, la hepatopatía aguda, la aterosclerosis y el traumatismo grave. Los neutrófilos, un subconjunto de los fagocitos, son candidatos adecuados para la eliminación de residuos, pero actualmente se desconocen los mecanismos de la eliminación del ADN necrótico. El objetivo principal del proyecto financiado con fondos europeos IMPACT es comprender de qué manera fagocitan los neutrófilos los residuos de ADN necrótico. El proyecto evaluará la hipótesis de que los neutrófilos utilizan receptores del complemento para fijarse y fagocitar ADN necrótico recubierto de complemento.
Objetivo
Cell death is inherently connected to the existence of multicellular organisms. Our body loses billions of cells a day due to thermal, mechanical or chemical damage in a cell death process with loss of plasma membrane integrity and pro-inflammatory properties known as necrosis. Organisms face necrosis frequently, thus, there must be specific pathways to remove the large amount of cellular debris left behind. In this way, it is no surprise that improper removal of cellular debris, such as DNA, is associated to inflammatory diseases as lupus erythematosus, acute liver injury, atherosclerosis and severe trauma. Removal of necrotic debris is thought to be mediated by phagocytes, although reports showing it are scarce. Neutrophils, a subset of phagocytes, are good candidates for debris removal since they are abundant and quickly recruited to necrotic sites. The means used by neutrophils to identify, internalize and degrade necrotic DNA are currently unknown, thus, the main objective of my project is to understand how neutrophils phagocytose and eliminate necrotic DNA debris. Neutrophils express the DNA-sensing receptor TLR9, which is not a phagocytic receptor. However, they also express very high levels of beta2 integrins such as CD11b/CD18, which act as adhesion molecule and as complement receptor (CR3). The release of necrotic DNA promotes complement activation in vivo through several pathways, therefore, my hypothesis is that neutrophils use beta2 integrins to bind and phagocytose complement-coated necrotic DNA. To assess the role of beta2 integrins, TLR9 and complement in phagocytosis of necrotic DNA by neutrophils, I will combine a novel in vitro method (DNA deposit in coverslip) with an in vivo approach (confocal intravital microscopy). I will also develop novel peptides for DNA labelling and modulation of phagocytosis, which I will use in both models. The findings of this project will directly favor the development of novel therapies for inflammatory diseases.
Ámbito científico
- medical and health scienceshealth sciencesinflammatory diseases
- natural sciencesbiological sciencesgeneticsDNA
- natural sciencesbiological sciencesbiochemistrybiomolecules
- medical and health sciencesclinical medicinecardiologycardiovascular diseasesarteriosclerosis
- natural sciencesphysical sciencesopticsmicroscopy
Palabras clave
Programa(s)
Régimen de financiación
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinador
3000 Leuven
Bélgica