Proyectos

Adverse intrauterine conditions, such as fetal growth restriction (FGR), increase the risk to develop cardiometabolic diseases in the adulthood. This concept has been called ‘Developmental Origins of Health and Disease’ (DOHaD) and relies on the activation of mechanisms sensing and signaling a diversity of stimuli during early development that later leads to higher risk of disease. The mechanisms that have been broadly suggested to be involved in these processes are epigenetic modifications in key gene promoters that could ‘record’ normal and abnormal perinatal stimuli. Intrauterine oxidative stress and chronic hypoxia are common features in FGR. Several cellular processes require the participation of pro-oxidant molecules which are normally neutralized by antioxidant defenses. However, under determined conditions, such as chronic hypoxia, the pro-oxidants overcome these defenses inducing oxidative stress. The latter is an important stimulus that regulates vascular function and cardiovascular physiology, playing a key role in the development of cardiovascular diseases, regulating negatively the bioavailability of the main vasodilator nitric oxide (NO). In addition, the vascular system presents a high phenotypic plasticity during life, which is modulated and restricted by epigenetic mechanisms (including DNA methylation, histone post-translational modifications, and micro RNAs). The higher cardiovascular risk in adults born with FGR can be traced back to a reduced arterial compliance in pre-pubertal subjects and a decreased peripheral endothelial-dependent vascular relaxation at birth. This endothelial dysfunction (ED) is also observed in FGR placental vessels, suggesting an early onset of ED that could be evidenced in systemic and placental arteries. Our studies in human placentae have demonstrated that ED in FGR can be modulated by oxidative stress and is associated with changes in proteome profile as well as an epigenetic-mediated regulation of eNOS expression. Similarly, in guinea pigs, we have found that ED in FGR is also occurring in the fetal arteries and is prevented by maternal treatment with antioxidants. Analysis of eNOS expression and Nos3 promoter DNA methylation profile in endothelial cells from the aorta and umbilical arteries of FGR guinea pigs shows common molecular markers of ED in FGR systemic and umbilical vessels which are reverted by a maternal antioxidant treatment. Altogether, these data support the role of oxidative stress in the epigenetic programming of ED in FGR and the potential predictive value of studying human umbilical arteries endothelial cells (HUAEC). However, there are no studies addressing the time course and origins of the ED in FGR and the participation of additional epigenetic mechanisms, such as miRNAs, in this process. Here, we put forward two inter-related hypotheses. First, that arterial endothelium from babies with FGR show a genomic DNA methylation signature along with an altered expression of miRNAs miR-21, miR-126 & miR-155, which contributes to changes in the expression of enzymes related to NO synthesis, endothelial dysfunction, and vascular remodeling. Second, that FGR has, during gestation, dynamic changes in the expression of miRNAs miR-21, miR-126 & miR-155 as an early response to hypoxia and oxidative stress in the fetus leading, in the long term, to endothelial dysfunction and vascular remodeling. These hypothesis will be tested in primary cultures of HUAEC from FGR neonates and validated using guinea pig and chick embryo models of FGR according to the following general aims (GA): GA-1 To demonstrate, in human umbilical artery endothelial cells, whether FGR is associated with an altered epigenetic regulation (i.e. increased levels of miR-21, miR-126 & miR-155 and a differential genomic DNA methylation) of NO-related enzymes (i.e. eNOS, DDAH1, Nrf2, Arg2, and HO-1), which modifies the response to hypoxia and impairs angiogenic capacity.GA-2 To demonstrate, in FGR guinea pigs, whether circulating levels of miR-21, miR-126 & miR-155 are dynamically regulated during the development of fetal vascular dysfunction and if the prevention of oxidative stress by an antioxidant administration to mothers, contributes to this regulation. GA-3 To demonstrate, in FGR chicken embryos, whether the silencing of miR-21, miR-126 and miR-155 expression modifies the endothelial and vascular dysfunction induced by chronic hypoxia and oxidative stress. Our expected outcome is to demonstrate that miRNAs miR-21, miR-126 & miR-155 participates in the early defense to hypoxia and oxidative stress in the FGR, but leading at long-term to ED. Further, we propose that regulation of these miRNAs during gestation could prevent these effects. This project is not only relevant to uncover the developmental mechanisms that determine short- and long-term vascular dysfunction, but also to open potential approaches for treatments in complicated pregnancies in humans. Combined, our program of work offers insights into mechanisms underlying the association between intrauterine hypoxia, oxidative stress and the increased risk of developing cardiovascular disease in later life, and possible interventions considering administration of therapeutic agents at critical stages of intrauterine development.

El proyecto tuvo como objetivos la formación continua de profesorado de cinco comunas de la región de O'Higgins en interculturalidad y uso del cine como herramienta de innovación didáctica en el aula de escuelas municipales. Los beneficiarios directos de Cineduka fueron 11 docentes de Artes Visuales y de Historia y Geografía y aproximadamente 700 estudiantes de 7º año básico de las escuelas participantes.

La construcción de un modelo predictivo, que podría dar origen a una herramienta de screening para ayudar al profesor a identificar un problema de salud mental en el aula y solicitar ayuda a los equipos de apoyo psico-pedagógico dentro del establecimiento. De igual forma, este proyecto podría dar origen a una cohorte de estudiantes que permita profundizar en el estudio de la relación salud mental – resultados académicos, con productos científicos (conocimiento) y tecnológicos de innovación, que apoyen el trabajo de los docentes y sus establecimientos.

Adverse intrauterine conditions, such as fetal growth restriction (FGR), increase the risk to develop cardiometabolic diseases in the adulthood. This concept has been called ‘Developmental Origins of Health and Disease’ (DOHaD) and relies on the activation of mechanisms sensing and signaling a diversity of stimuli during early development that later leads to higher risk of disease. The mechanisms that have been broadly suggested to be involved in these processes are epigenetic modifications in key gene promoters that could ‘record’ normal and abnormal perinatal stimuli. Intrauterine oxidative stress and chronic hypoxia are common features in FGR. Several cellular processes require the participation of pro-oxidant molecules which are normally neutralized by antioxidant defenses. However, under determined conditions, such as chronic hypoxia, the pro-oxidants overcome these defenses inducing oxidative stress. The latter is an important stimulus that regulates vascular function and cardiovascular physiology, playing a key role in the development of cardiovascular diseases, regulating negatively the bioavailability of the main vasodilator nitric oxide (NO). In addition, the vascular system presents a high phenotypic plasticity during life, which is modulated and restricted by epigenetic mechanisms (including DNA methylation, histone post-translational modifications, and micro RNAs). The higher cardiovascular risk in adults born with FGR can be traced back to a reduced arterial compliance in pre-pubertal subjects and a decreased peripheral endothelial-dependent vascular relaxation at birth. This endothelial dysfunction (ED) is also observed in FGR placental vessels, suggesting an early onset of ED that could be evidenced in systemic and placental arteries. Our studies in human placentae have demonstrated that ED in FGR can be modulated by oxidative stress and is associated with changes in proteome profile as well as an epigenetic-mediated regulation of eNOS expression. Similarly, in guinea pigs, we have found that ED in FGR is also occurring in the fetal arteries and is prevented by maternal treatment with antioxidants. Analysis of eNOS expression and Nos3 promoter DNA methylation profile in endothelial cells from the aorta and umbilical arteries of FGR guinea pigs shows common molecular markers of ED in FGR systemic and umbilical vessels which are reverted by a maternal antioxidant treatment. Altogether, these data support the role of oxidative stress in the epigenetic programming of ED in FGR and the potential predictive value of studying human umbilical arteries endothelial cells (HUAEC). However, there are no studies addressing the time course and origins of the ED in FGR and the participation of additional epigenetic mechanisms, such as miRNAs, in this process. Here, we put forward two inter-related hypotheses. First, that arterial endothelium from babies with FGR show a genomic DNA methylation signature along with an altered expression of miRNAs miR-21, miR-126 & miR-155, which contributes to changes in the expression of enzymes related to NO synthesis, endothelial dysfunction, and vascular remodeling. Second, that FGR has, during gestation, dynamic changes in the expression of miRNAs miR-21, miR-126 & miR-155 as an early response to hypoxia and oxidative stress in the fetus leading, in the long term, to endothelial dysfunction and vascular remodeling. These hypothesis will be tested in primary cultures of HUAEC from FGR neonates and validated using guinea pig and chick embryo models of FGR according to the following general aims (GA): GA-1 To demonstrate, in human umbilical artery endothelial cells, whether FGR is associated with an altered epigenetic regulation (i.e. increased levels of miR-21, miR-126 & miR-155 and a differential genomic DNA methylation) of NO-related enzymes (i.e. eNOS, DDAH1, Nrf2, Arg2, and HO-1), which modifies the response to hypoxia and impairs angiogenic capacity.GA-2 To demonstrate, in FGR guinea pigs, whether circulating levels of miR-21, miR-126 & miR-155 are dynamically regulated during the development of fetal vascular dysfunction and if the prevention of oxidative stress by an antioxidant administration to mothers, contributes to this regulation. GA-3 To demonstrate, in FGR chicken embryos, whether the silencing of miR-21, miR-126 and miR-155 expression modifies the endothelial and vascular dysfunction induced by chronic hypoxia and oxidative stress. Our expected outcome is to demonstrate that miRNAs miR-21, miR-126 & miR-155 participates in the early defense to hypoxia and oxidative stress in the FGR, but leading at long-term to ED. Further, we propose that regulation of these miRNAs during gestation could prevent these effects. This project is not only relevant to uncover the developmental mechanisms that determine short- and long-term vascular dysfunction, but also to open potential approaches for treatments in complicated pregnancies in humans. Combined, our program of work offers insights into mechanisms underlying the association between intrauterine hypoxia, oxidative stress and the increased risk of developing cardiovascular disease in later life, and possible interventions considering administration of therapeutic agents at critical stages of intrauterine development.

La construcción de un modelo predictivo, que podría dar origen a una herramienta de screening para ayudar al profesor a identificar un problema de salud mental en el aula y solicitar ayuda a los equipos de apoyo psico-pedagógico dentro del establecimiento. De igual forma, este proyecto podría dar origen a una cohorte de estudiantes que permita profundizar en el estudio de la relación salud mental – resultados académicos, con productos científicos (conocimiento) y tecnológicos de innovación, que apoyen el trabajo de los docentes y sus establecimientos.

La enfermedad de Chagas es una de las enfermedades parasitarias más importante en Latinoamérica, afectando a aproximadamente 6 millones de personas. Esta enfermedad es causada por el protozoo hemoflagelado Trypanosoma cruzi, el cual presenta un ciclo de vida indirecto que incluye insectos hematófagos y mamíferos. Dadas las características de abundancia y asociación al peridomicilio del vector silvestre Mepraia spinolai, su la amplia distribución en Chile y las variadas especies de mamíferos que pueden ser identificados como fuente de infección para este vector, cobra importancia realizar estudios que relacionen a esta especie con sus potenciales hospederos. Del punto de vista epidemiológico, esto es importante para evitar indirectamente la transmisión de T. cruzi al hombre, al disminuir la propagación de este vector. Objetivos Puesto que se eliminó al vector Triatoma infestans de los domicilios en Chile, los estudios en los vectores silvestres cobran cada día más importancia, sobre todo en áreas donde se establece el contacto con el hombre. El objetivo principal de esta investigación es evaluar la interacción entre el tipo de hospedero y la infección por T. cruzi en M. spinolai, determinando su repercusión en la eficacia biológica de este vector endémico. Metodología La evaluación de la eficacia biológica del vector se realizará a través de la determinación de la sobrevivencia poblacional de M. spinolai, de su tiempo de desarrollo hasta estado adulto y de su fecundidad. Esto será comparado según su dieta específica (conejo, rata, cabra o gallina) y su estatus de infección por T. cruzi. Cada grupo será alimentado con un determinado hospedero (sin infección) a lo largo de toda su vida, desde el estadio II hasta adulto. Los triatominos infectados serán capturados en terreno, y su infección por T. cruzi será determinada en deyecciones mediante PCR en tiempo real. Los triatominos no infectados serán obtenidos de una colonia de laboratorio generada a partir de insectos no infectados, libres de infección. Resultados Esperados Como resultado general, se podrá evaluar la eficacia biológica de esta especie al alimentarse con animales disponibles en el peridomicilio, y se podrá discriminar si las diferencias según hospedero varían en el caso de que los vectores estén infectados. Se espera una mayor eficacia biológica por parte del grupo de M. spinolai libres de infección respecto al grupo de aquellos infectados por T. cruzi. Por otra parte, se espera que el tipo de hospedero del que se alimentan los insectos triatominos también genere diferencias en la eficacia biológica del vector, principalmente determinadas por las características sanguíneas de cada especie de vertebrado. El conocer qué especie favorece el crecimiento de las poblaciones de M. spinolai, permitirá aconsejar sobre medidas de manejo de animales a los pobladores de las regiones endémicas – principalmente rurales - que apunten a reducir el riesgo de proliferación de esta especie en la cercanía de sus hogares.

La construcción de un modelo predictivo, que podría dar origen a una herramienta de screening para ayudar al profesor a identificar un problema de salud mental en el aula y solicitar ayuda a los equipos de apoyo psico-pedagógico dentro del establecimiento. De igual forma, este proyecto podría dar origen a una cohorte de estudiantes que permita profundizar en el estudio de la relación salud mental – resultados académicos, con productos científicos (conocimiento) y tecnológicos de innovación, que apoyen el trabajo de los docentes y sus establecimientos.

La construcción de un modelo predictivo, que podría dar origen a una herramienta de screening para ayudar al profesor a identificar un problema de salud mental en el aula y solicitar ayuda a los equipos de apoyo psico-pedagógico dentro del establecimiento. De igual forma, este proyecto podría dar origen a una cohorte de estudiantes que permita profundizar en el estudio de la relación salud mental – resultados académicos, con productos científicos (conocimiento) y tecnológicos de innovación, que apoyen el trabajo de los docentes y sus establecimientos.

Proyecto GEF-Montaña/CONAF

La construcción de un modelo predictivo, que podría dar origen a una herramienta de screening para ayudar al profesor a identificar un problema de salud mental en el aula y solicitar ayuda a los equipos de apoyo psico-pedagógico dentro del establecimiento. De igual forma, este proyecto podría dar origen a una cohorte de estudiantes que permita profundizar en el estudio de la relación salud mental – resultados académicos, con productos científicos (conocimiento) y tecnológicos de innovación, que apoyen el trabajo de los docentes y sus establecimientos.