Browsing by Author "Amigo, Julio"
Now showing 1 - 4 of 4
Results Per Page
Sort Options
- ItemImatinib therapy blocks cerebellar apoptosis and improves neurological symptoms in a mouse model of Niemann-Pick type C disease(WILEY, 2008) Alvarez, Alejandra R.; Klein, Andres; Castro, Juan; Cancino, Gonzalo I.; Amigo, Julio; Mosqueira, Matias; Vargas, Lina M.; Yevenes, L. Fernanda; Bronfman, Francisca C.; Zanlungo, SilvanaNiemann-Pick type C (NPC) disease is a fatal autosomal recessive disorder characterized by the accumulation of free cholesterol and glycosphingo-lipids in the endosomal-lysosomal system. Patients with NPC disease have markedly progressive neuronal loss, mainly of cerebellar Purkinje neurons. There is strong evidence indicating that cholesterol accumulation and trafficking defects activate apoptosis in NPC brains. The purpose of this study was to analyze the relevance of apoptosis and particularly the proapoptotic c-Abl/p73 system in cerebellar neuron degeneration in NPC disease. We used the NPC1 mouse model to evaluate c-Abl/p73 expression and activation in the cerebellum and the effect of therapy with the c-Abl-specific inhibitor imatinib. The proapoptotic c-Abl/p73 system and the p73 target genes are expressed in the cerebellums of NPC mice. Furthermore, inhibition of c-Abl with imatinib preserved Purkinje neurons and reduced general cell apoptosis in the cerebellum, improved neurological symptoms, and increased the survival of NPC mice. Moreover, this prosurvival effect correlated with reduced mRNA levels of p73 proapoptotic target genes. Our results suggest that the c-Abl/p73 pathway is involved in NPC neurodegeneration and show that treatment with c-Abl inhibitors is useful in delaying progressive neurodegeneration, supporting the use of imatinib for clinical treatment of patients with NPC disease.
- ItemMecanismos de activación y coordinación de las señales de Ca2+ involucradas en la migración de las células endoteliales y la angiogénesis(2020) Espinoza Amador, Hilda Andrea; Figueroa, Xavier; Amigo, Julio; Pontificia Universidad Católica de Chile. Facultad de Ciencias BiológicasLa migración endotelial es clave para la angiogénesis y depende de un incremento en la [Ca2+]i. El intercambiador Na+-Ca2+ (NCX) es crítico en el control del Ca2+ y podría contribuir al aumento en la [Ca2+]i de las células endoteliales a través de la activación de su modo reverso mediante el acoplamiento con los canales de Na+ dependientes de voltaje (Nav). La comunicación vía uniones comunicantes coordina los cambios en la [Ca2+]i, pero no se ha evaluado la participación de los hemicanales en este proceso. En esta tesis se descubrió un nuevo mecanismo de regulación de la señalización de Ca2+ endotelial durante la angiogénesis, el cual depende de la activación secuencial de los canales Nav sensibles a TTX, Nav1.2 y Nav1.6, del modo reverso del NCX y los hemicanales formados por Cx43. La activación del modo reverso del NCX mediada por los canales Nav sensibles a TTX lleva a un aumento inicial de la [Ca2+]i, la cual induce la producción de NO y la apertura de los hemicanales formados por Cx43 a través de la S-nitrosilación de esta Cx. Además, este mecanismo depende de la redistribución celular de los canales Nav1.2 y los hemicanales formados por Cx43 junto a las caveolas hacia la parte posterior de las células endoteliales, concentrando de esta forma la señalización de Ca2+ en esta región celular. Estos resultados demuestran que los canales Nav sensibles a TTX y los hemicanales formados por Cx43 son fundamentales en el desarrollo de la migración endotelial y la angiogénesis.
- ItemThe Reprimo gene family member, reprimo-like (rprml), is required for blood development in embryonic zebrafish(2019) Stanic, Karen; Reig, German; Figueroa, Ricardo J.; Retamal, PedroA.; Wichmann Pérez, Ignacio Alberto; Opazo, JuanC.; Owen, Gareth Ivor; Corvalán R., Alejandro; Concha, Miguel L.; Amigo, JulioThe Reprimo gene family comprises a group of sing le-exon genes for which their physiological function remains poorly understood. Heretofore, mammalian Reprimo (RPRM) has been described as a putative p53-dependent tumor suppressor gene that functions at the G2/M cell cycle checkpoint. Another family member, Reprimo-like (RPRML), has not yet an established role in physiology or pathology. Importantly, RPRML expression pattern is conserved between zebrafish and human species. Here, using CRISPR-Cas9 and antisense morpholino oligonucleotides, we disrupt the expression of rprml in zebrafish and demonstrate that its loss leads to impaired definitive hematopoiesis. The formation of hemangioblasts and the primitive wave of hematopoiesis occur normally in absence of rprml Later in development there is a significant reduction in erythroid-myeloid precursors (EMP) at the posterior blood island (PBI) and a significant decline of definitive hematopoietic stem/progenitor cells (HSPCs). Furthermore, loss of rprml also increases the activity of caspase-3 in endothelial cells within the caudal hematopoietic tissue (CHT), the first perivascular niche where HSPCs reside during zebrafish embryonic development. Herein, we report an essential role for rprml during hematovascular development in zebrafish embryos, specifically during the definitive waves of hematopoiesis, indicating for the first time a physiological role for the rprml gene.
- ItemThe reprimo-like gene is an epigenetic-mediated tumor suppressor and a candidate biomarker for the non-invasive detection of gastric cancer(2020) Alarcón Alarcón, María Alejandra; Olivares, W.; Córdova Delgado, M.; Wichmann Pérez, Ignacio Alberto; Amigo, Julio; Norero Muñoz, Enrique; Riquelme Pérez, Arnoldo; Garrido S., Marcelo; Owen, Gareth Ivor; Corvalán R., Alejandro; Muñoz-Medel, M.; Mayo, T. de; Carrasco-Aviño, G.; Landeros, N.; Villarroel Espíndola, F.