Proyectos

The brain is an energy intensive organ that requires a robust supply of nutrients and oxygen. The vasculature irrigating the brain is a huge and complex network of blood vessels fulfilling this requirement, while also protecting the neural tissue from blood-borne toxic substances. This regulated nutrient supply is accomplished by the formation of a highly selective molecular barrier, termed the blood-brain barrier (BBB). Dysfunction of the BBB or malformations of the vascular network are associated with pathological conditions that impair brain function, and can lead to death. Thus, appropriate morphogenesis and establishment of the brain vasculature is necessary for a healthy life. The brain vasculature forms during intrauterine development, matching brain growth in this same period. Anatomically, blood vessels grow first surrounding the brain primordium and then penetrate the parenchyma until they vascularize the periventricular zone. The molecular regulation of this patterned growth is not completely understood. Several signaling pathways are known to be involved in brain angiogenesis, including WNT, TGF-β, Hh, and NOTCH, which differentially regulate vascular growth. Recently, cholesterol has been shown to modulate angiogenic growth in other vascular beds by regulating the activity of the NOTCH pathway, suggesting that cholesterol levels could influence developmental angiogenesis in the brain. Interestingly, cholesterol is also required for signal transduction of the Hh pathway. In preliminary in vitro experiments, we have observed that brain endothelial cells activate an angiogenic program after cholesterol depletion. Here, we will extend those studies to in vivo models to determine the role of cholesterol in developmental brain angiogenesis. We propose that an increase in vascular cell cholesterol activates NOTCH and attenuates Hh signaling pathways, restricting sprouting angiogenesis and blood-brain barrier formation in mouse embryo brain vasculature. To test this hypothesis, we will study mouse embryos with altered cholesterol levels by dietary, pharmacological, and genetic manipulations. We expect these manipulations to induce a reduction or an increase in cholesterol levels in the brain vasculature during embryonic development, which we will evaluate by measuring cholesterol content in isolated vascular fragments. In all these models, we will (Specific aim 1) study vascularization in the brain during intrauterine development using immunofluorescence with specific antibodies against endothelium proteins. In addition, we will measure the levels of transcript and proteins of general key regulators of angiogenesis in isolated vascular fragments, using qPCR and Western blot. We will (Specific aim 2) also evaluate the state of the BBB in the brain vasculature of these models at a fetal stage when the barrier is already formed and functional. For this, we will use immunofluorescence to detect the presence of marker proteins of the BBB in vascular fragments, and we will measure their levels by Western blot. Further, we will test the functionality of the barrier by injecting a fluorescent tracer and evaluating its extravasation in the brain. Finally, we will (Specific aim 3) determine the activation of the NOTCH and Hh pathways in the brain vasculature of the models at the stage of maximal angiogenesis. We will use qPCR and Western blot to measure the levels of marker genes and proteins for these two pathways in vascular fragments, and Proximity Ligation In Situ Hybridization in tissue sections to evaluate the transcript levels of those markers in situ. We expect that the different models of dietary, pharmacological, and genetic interventions will increase or reduce cholesterol levels in the brain vasculature. These changes are expected to correlate with opposing effects on angiogenesis in the brain during development (i.e. low cholesterol will increase angiogenesis, while high cholesterol will inhibit it). In the same way, we expect that distinct cholesterol levels will have opposing effects on the integrity of the BBB. These changes in angiogenesis and BBB function are expected to be associated with concomitant disruption of the NOTCH and Hh pathways. In summary, in this proposal we aim to cover a knowledge gap regarding the role of cholesterol in the regulation of developmental angiogenesis in the brain. These experiments may uncover new mechanisms driving vascular growth and barrier establishment in the brain, which could lead to new strategies for the prevention and treatment of pathologies involving the brain vasculature.

The world's transition to using cleaner energy sources to address climate change has led to a sharp rise in the demand for base and precious metals. Consequently, discovering new ore deposits to meet this growing demand and prevent supply shortages has emerged as one of the greatest challenges of the 21st century. Discovery of new magmatic-hydrothermal ore deposits can be improved based on a fundamental understanding of the geological processes that control the flux and focusing of ore-constituting elements in the Earth’s crust, and by identifying the differences between the bulk-rock and mineral chemistry of ore-forming and ordinary—barren—granitoids. Large metal anomalies in the Earth’s upper crust, such as porphyry copper-(molybdenum) deposits (PCDs), occur in intimate association with oxidized and water-rich arc magmatism in subduction zones. However, these deposits occur in restricted crustal domains and form in response to specific tectono-magmatic events, indicating that not all arc magmas have the same ore-forming potential. Understanding why only some magmas produced large PCDs while most other arc magmas remain barren is a fundamental scientific question and key to developing efficient exploration strategies. The volatile element composition of arc magmas, including water, sulfur, and halogens such as chlorine and fluorine, as well as their oxygen fugacity, exert a critical control on their ore-forming potential (i.e., ore fertility). These components are not only key to the complexation and transport of ore metals during hydrothermal activity, but also influence the amount of ore metals transported by magmas and the efficiency to which they are transferred from magmas to exsolved fluids. Magmatic differentiation in lower crustal hot zones beneath thick crustal regions is expected to enhance the volatile element budget and oxygen fugacity of evolving magmas that are discharged to the upper crust. This occurs due to the accumulation of incompatible volatile elements during successive cycles of recharge by mafic magmas and crystallization, facilitated by the deeper and hotter conditions beneath thicker arc crusts. As such, an increasingly recognized hypothesis holds that ore-forming magmas display a particularly increased budget of volatile elements and higher oxygen fugacities when compared to barren arc magmas, and that this is largely influenced by the arc crust thickness. The proposed work will test this hypothesis by focusing on the Miocene to Mio-Pliocene magmatism and associated world-class PCD mineralization in the Andes of central Chile. From the Early Miocene to the Mio-Pliocene, the arc segment located between latitudes ~33–34.5° S in the Andes of central Chile has seen a continued increase in crustal thickness and has evolved from being barren in the Early Miocene to producing some of the largest PCDs of the world in the Mio-Pliocene, such as El Teniente and Rio Blanco-Los Bronces. This geological scenario and the spatial and age distribution of the associated outcropping intrusive rocks offer a unique opportunity to investigate the temporal evolution of the volatile composition of magmas and its consequences for ore fertility. The goal of this proposal is to examine, adopting a regional scale perspective, the evolution in the volatile composition and oxygen fugacity of magmas produced in this arc segment and its relationship to magmatic ore fertility, as well as how this may have been influenced by changes in crustal thickness. To achieve this, I will sample an extensive suite of granitoids that represent a continuum from Early Miocene to Mio-Pliocene magmas, including porphyry-forming intrusions. By combining zircon petrochronology, apatite, biotite, and amphibole mineral chemistry, in conjunction with the bulk-rock composition of intermediate to felsic intrusive rocks, I will be able to constrain relative changes in the hydration state, sulfur contents, halogen and oxygen fugacities, as well as in their associated crustal thickness during the evolution of the selected arc segment. This will be done by implementing a combination of cutting-edge analytical techniques, including synchrotron-based sulfur X-ray absorption near edge structure spectroscopy, electron probe microanalysis, (laser ablation) inductively coupled plasma mass spectrometry, and X-ray fluorescence spectrometry. I aim at (1) testing the differences in the volatile composition of barren and ore-forming intrusive rocks; (2) determining whether there is a gradual change in the volatile systematics of magmas during the evolution of the studied arc segment; and (3) analyzing the relationship between variations in crustal thickness and the volatile composition of associated magmas. The results of this proposal will lead to a better understanding of the magmatic controls underpinning the formation of giant PCDs and will provide valuable insights into identifying the differences between the bulk-rock and mineral chemistry of ore-forming and barren granitoids as tools for vectoring mineralized regions.

Proyecto de investigación que apunta al estudio de practicas sostenibles para el manejo de sistemas silvopastoril en el secano costero. El proyecto involucra el estudio de la materia orgánica del suelo, además de una serie de variables que pueden impactar el manejo de los agroecosistemas

Non-communicable diseases (NCDs) are responsible for 74% of worldwide human deaths, with cardiovascular causes in the first place (1). NCDs are determined by a combination of environmental, genetic and epigenetic factors. In fact, adverse intrauterine conditions, such as reduced oxygen availability (hypoxia) and oxidative stress, can increase the risk of developing diseases during life, a phenomenon known as Fetal Programming or Developmental Origins of Health and Disease (DOHaD). Intrauterine hypoxia (IUH) affects most of the pregnancies in high altitudes populations (> 2500m) (2-4) and 3-4% in lowlands, with uteroplacental and developmental complications (4,5). We, and a couple of others, have recently shown that IUH determines cardiovascular oxidative stress during lifespan affecting endothelial function and vasodilator capacity, similar to what is seen with aging. The hypoxia-induced responses during development are responsible for fetal survival, but also determine mechanisms that program postnatal cardiovascular function that may increase cardiovascular health risks and accelerate aging (6). This proposal aims to determine the mechanisms and trace the origins and outcomes of cardiovascular dysfunction resulting from intrauterine hypoxia and oxidative stress, and further identify the interrelated senescence mechanisms in the heart and blood vessels. To assess the aforementioned, we will study the effects of IUH on cardiovascular aging along lifespan, as important regulators of the function, structure and biomechanical properties of the cardiovascular system.

Non-communicable diseases (NCDs) are responsible for 74% of worldwide human deaths, with cardiovascular causes in the first place (1). NCDs are determined by a combination of environmental, genetic and epigenetic factors. In fact, adverse intrauterine conditions, such as reduced oxygen availability (hypoxia) and oxidative stress, can increase the risk of developing diseases during life, a phenomenon known as Fetal Programming or Developmental Origins of Health and Disease (DOHaD). Intrauterine hypoxia (IUH) affects most of the pregnancies in high altitudes populations (> 2500m) (2-4) and 3-4% in lowlands, with uteroplacental and developmental complications (4,5). We, and a couple of others, have recently shown that IUH determines cardiovascular oxidative stress during lifespan affecting endothelial function and vasodilator capacity, similar to what is seen with aging. The hypoxia-induced responses during development are responsible for fetal survival, but also determine mechanisms that program postnatal cardiovascular function that may increase cardiovascular health risks and accelerate aging (6). This proposal aims to determine the mechanisms and trace the origins and outcomes of cardiovascular dysfunction resulting from intrauterine hypoxia and oxidative stress, and further identify the interrelated senescence mechanisms in the heart and blood vessels. To assess the aforementioned, we will study the effects of IUH on cardiovascular aging along lifespan, as important regulators of the function, structure and biomechanical properties of the cardiovascular system.

The quality of fetal and early post-natal environment influences lifelong health and predicts the risk for a range of non-communicable chronic diseases (NCDs). These observations form the basis of the "Developmental Origins of Health and Disease" (DOHaD hypothesis), which indicates that the intrauterine signals that compromise fetal growth also act to "program" tissue differentiation in a manner that predisposes later illnesses. Interestingly, the DOHaD hypothesis asserts that some aging-associated diseases that occur in adults are closely related to the development and conditions in the intrauterine environment. Thus, aging and aging-associated diseases can be viewed, at least in part, as the result of a developmental program activated early in embryogenesis and persists throughout the organism's lifespan. On the other hand, one of the main consequences of this programming is Fetal Growth Restriction (FGR) and which remains a leading cause of perinatal morbidity and mortality, affecting about 10% of pregnancies, but the incidence is reportedly sixfold greater in low-income countries depending on the region surveyed's nutrition and health access availability. FGR is clinically defined as a fetal weight below the 10th percentile of normal for gestational age, associated with some loss of fetal-placental blood flow diagnosed by ultrasound, and it is a condition in which the potential growth of the fetus is negatively influenced by environmental and maternal factor; the short-term consequences of FGR are low birth weight (LBW) and the corresponding phenotype, which is associated with increased perinatal morbidity and mortality. Besides, the long-term effects include a 2 to 3-fold increase in the risk of developing cerebrovascular disease in adulthood. Indeed, many neurodevelopmental dysfunctions originated in the antenatal period, but few studies have focused on how growth restriction interferes with normal brain development of the blood-brain barrier (BBB) in the FGR neonate. The BBB is a cellular network formed by a monolayer of neuro-endothelial and mural cells. The BBB regulates the transport of molecules into and out of the central nervous system (CNS) (selective permeability and integrity of the BBB). In cerebrovascular aging, BBB breakdown and dysfunction lead to leakages of components into the central nervous system (CNS), contributing to neurological deficits; growing evidence from genomic data shows that FGR vascular dysfunction is mediated by aging, with a series of prominent hallmarks, including genetic and epigenetic alterations. These aging-associated epigenetic changes include DNA methylation, histone modification, chromatin remodeling, and non-coding RNA (ncRNA) regulation; however, how this mechanism regulates the aging process and contributes to aging-related BBB dysfunction remains elusive. We hypothesize that the impaired fetal growth conditions associated with epigenetic programming of aging-related DNA methylation, chromatin remodeling, and miRNA-omic profile of complex junctional genes in the neuro-endothelium, which can alter BBB integrity and permeability, increasing cerebral damage which impacts the perinatal and adulthood neurocognitive function. This hypothesis will be addressed by the study of the effects of gestational chronic hypoxia on the aging epigenetic programming of gene expression of junctional complexes: Tight junction, adherens junction, and Gap junction family’s molecules, as important regulators of the permeability para and transcellular of the BBB. For this, we will use a well-established Guinea pig model of cerebrovascular programming (DOHaD model) to demonstrate DNA methylation shift, chromatin remodeling, miRNA-omic profile, and transcriptomic analyses in neuro-endothelial cells isolated from cortex and hippocampus from animals gestated under hypobaric hypoxia at two stages of life (juvenile period and adulthood). The methodology for this project is an in vivo assess locomotor, exploratory activity, and memory acquisition evaluation, and in vitro determinations of epigenetic regulation of aging in BBB from the cortex, hypothalamus, and neuro- endothelial cell culture primary at different stages of life in animals gestated under hypoxia. Our expected outcome is to improve the knowledge about neuro-endothelial epigenetic programming by aging induced by the FGR and enhance the characterization of those epigenomic patterns and mechanisms associated with BBB breakdown by intrauterine hypoxia. This project aims to demonstrate that the effect of gestational hypoxia can accelerate the permeability of the BBB by epigenetic mechanisms not yet studied and that these changes continue throughout life, producing further deterioration of brain function

Durante las últimas décadas, la expectativa de vida promedio ha aumentado dramáticamente, mientras que la salud no ha aumentado proporcionalmente. Para Chile se espera que para el 2050 el número de adultos mayores superará el 30% de la población con un incremento del 109% respecto al 2015, superando el 75% proyectado para la población mundial. Entender el proceso de envejecimeinto y encontrar marcadores biológicos con capacidad diagnóstica y pronóstica, permitirá promover estrategias para aumentar el número de años de vida saludable, disminuyendo los gastos en salud asociado al envejecimiento. Varios estudios han permitido avanzar y entender los mecanismos moleculares de pérdidad de función muscular durante el evenjecimiento, más conocida como sarcopenia. Sin embargo, la complejidad del proceso y el insuficiente conocimiento de los mecanismos subjacentes dificultan el diseño de estrategias terapéuticas eficaces. Hasta el momento, la actividad física y el ejercicio siguen siendo la estrategia más eficaz para previnir y tratar la sarcopenia. Por lo cual, identificar nuevos biomarcadores musculares en combinación con marcadores clínicos bien establecidos de parámetros físicos y funcionales, fortalecería la actual evaluación geriátrica, al utilizar un enfoque interdiciplinario. Los microRNA (miRNA, 18–25 nt de largo) han ganado interés debido a que son moléculas altamente conservadas en todas las especies, y actúan como reguladores positivos y/o negativos de la expresión génica. Entender la relación reguladora directa entre los miARN y el ARN mensajero (mRNA) desempeña en el músculo esquelética es fundamentaltanto para el proceso de transcripción del ARNm y traducción de proteínas como para entender el deterioro de la función muscular. Sin embargo, la regulación de la red post-transcripcional miARN-ARNm y los mecanismos genéticos involucrados en el proceso de envejecimiento del músculo esquelético humano están lejos de ser elucidados. En el presente estudio, nuestro objetivo es explorar e integrar coperfiles emparejados de miARN y ARNm durante la pérdida de función muscular producidad durante el envejecimeinto en personas mayores. Este análisis integral permitirá la identificación de nuevos blancos de miARN y estrategias reguladoras que controlan la expresión génica en la pérdidad de función del músculo esquelético y cómo éstas son modificadas por el entrenamiento de fuerza. Se hipotetiza que existen redes de regulación post-transcripcional miRNA/mRNA que se expresan de manera diferencial en el músculo esquelético de personas jóvenes y personas mayores, que estarían asociadas con cambios en la función muscular durante el envejecimiento. Además, el entrenamiento de fuerza modifica estas redes de regulación, lo que podría contribuir a la mejora de la función muscular y la prevención o atenuación de la sarcopenia. Objetivos generales - Identificar las redes de regulación post-transcripcional miRNA/mRNA involucradas en la pérdida de función musclular en personas mayores que son moduladas por un entrenamiento de fuerza, para proponer nuevos biomarcadores de función muscular durante el envejecimeinto que se correlacionan con parámetros clínicos/funcionales. Objetivos específicos 1. Determinar las redes de regulación post-transcripcional miRNA/mRNA que se expresan diferencialmente en el músculo esquelético de personas jóvenes y personas mayores. 2. Identificar las redes de regulación post-transcripcional miRNA/mRNA que se modifican después de 12 semanas de entrenamiento de fuerza en personas mayores 3. Correlacionar las redes miRNA/mRNA identificadas con parámetros bioquímicos, físicos y funcionales de función muscular, antes y después de 12 semanas de entrenamiento de fuerza en personas mayores Este proyecto busca Identificar nuevos biomarcadores de función muscular durante el envejecimiento, podrían ser utilizados en futuros estudios y en la práctica clínica para evaluar la salud muscular en personas mayores. Además, de contribuir a una mejor comprensión de los mecanismos moleculares que subyacen a la pérdida de masa muscular en el envejecimiento y cómo la intervención del entrenamiento de fuerza puede modificar esos mecanismos. Finalmente, el uso de tecnologías avanzadas de secuenciación (mARN y miARN) y bioinformática permitirá impulsar el desarrollo y la mejora de técnicas de secuenciación y análisis de datos en el campo de la genómica y la transcriptómica en el área del envejecimiento, como también, promover la colaboración a nivel nacional e internacional a través de las bases de datos y recursos bioinformáticos generados que estarán a disposición de investigadores del área.

La formación de ciudadanos y ciudadanas capaces de afrontar los desafíos sociales y tecnológicos actuales requiere de capacidades matemáticas que van más allá del foco tradicional en contenidos específicos y que den paso, en cambio, al desarrollo de habilidades matemáticas y de pensamiento matemático. La realidad educativa chilena evidencia que los logros académicos en matemática han estado estancados por varios años, para luego sufrir un retroceso durante el período de pandemia. Si bien, desde 2012, los lineamientos curriculares de la asignatura de Matemática incluyen explícitamente un foco en pensamiento matemático y objetivos de aprendizaje ligados a cuatro habilidades, docentes de todos los niveles educativos tienden a carecer de herramientas y competencias para desarrollarlas. Los numerosos desafíos de la formación docente de pregrado, posgrado y formación continua se profundizan al considerar la realidad de regiones distintas a la Metropolitana. En este contexto, se destaca la creación en 2015 de la Universidad de O’Higgins como una decisión para potenciar el acceso a la educación superior de una región históricamente postergada. En la actualidad, la Universidad de O’Higgins cuenta con una carrera de Pedagogía en Matemática, formación especializada en matemática en su carrera de Pedagogía en Educación Básica, y con un proyecto de programa de Magíster en Enseñanza y Aprendizaje de la Matemática cuya implementación se proyecta para 2024. Alrededor de estos programas, se ha generado un equipo de investigadores(as) y docentes proveniente de diversas disciplinas –grupo de investigación GeaMat– que comparten un interés común por mejorar la educación matemática a través de empoderar a los y las docentes con herramientas y competencias para el desarrollo de habilidades matemáticas y el pensamiento matemático en distintos niveles del sistema educativo. La presente propuesta busca consolidar estos vínculos a través de la articulación de una Red académica multidisciplinaria, nacional e internacional, que potencie la investigación, la docencia y la formación de capital humano avanzado en educación matemática, con foco particular en el estudio y desarrollo de habilidades matemáticas y el pensamiento matemático. El equipo chileno, liderado por la Universidad de O’Higgins con participación de la Universidad Católica de la Santísima Concepción y la Universidad Metropolitana de Ciencias de la Educación, confluirá con un equipo de investigadores(as) de España, Costa Rica y Bélgica. Los miembros del equipo nacional cuentan con un historial de vinculación previa con los(as) investigadores(as) del extranjero, que se extiende en varios casos por más de cinco años y se continuará articulando a través de esta propuesta buscando potenciar la realización de iniciativas de investigación y desarrollo conjuntas, así como fortalecer la formación de pre y posgrado en el área en las instituciones nacionales. En particular, se espera como resultados de este proyecto: 1) la consolidación del grupo de investigación GeaMat, creado recientemente en la Universidad de O’Higgins, 2) el desarrollo de dos proyectos de investigación de forma colaborativa en la Red, 3) la realización de reuniones de intercambio de experiencias de formación de pre y posgrado en educación matemática, y 4) la elaboración de un documento con recomendaciones para el desarrollo de habilidades y pensamiento matemático en diferentes contextos educativos. De esta forma, se espera que esta propuesta produzca impactos tanto en el ámbito científico como en el ámbito educativo regional y nacional.

El objetivo principal de este proyecto es analizar y comprender cómo la interacción entre escuela y familia puede generar altas expectativas compartidas para reducir las brechas educativas. Esto considerando dos perspectivas, una local y aplicada y otra global y con foco en el desarrollo de conocimiento básico. Desde la perspectiva local, tenemos que Chile, y en particular la Región de O'Higgins, presenta desafíos complejos en términos de desigualdades educativas asociadas a factores socioeconómicos y de ruralidad. Las brechas educativas son un problema persistente, asociado a un sistema educacional extremadamente segregado. Por otra parte, desde una perspectiva global, las desigualdades educativas son un problema munidal, con especificidades de cada contexto, y es necesario entender qué tipos de relaciones familia-escuela permiten reducir desigualdades. Además, uno de los objetivos de desarrollo sostenible es alcanzar una educación de calidad para todos y todas, y este proyecto apunta al logro de ese objetivo