Proyectos

Retinal vascular diseases are major causes of vision loss in the United States and around the world. To better treat these disorders, we need to understand the signaling pathways that control the growth and integrity of retinal blood vessels. Our recent publications and preliminary data detail a novel angiogenic signaling system centered around heme, a co-factor critical for oxygen transport, metabolism, and gene transcription. We found that heme promotes angiogenic growth in the retina by regulating tip/stalk selection, and that reduced heme production or import leads to reduced retinal vascularization and tissue hypoxia, similar to other retinal vasculopathies including retinopathy of prematurity, choroidal neovascularization, and the rare but important exudative vitreoretinopathies. Furthermore, we found that VEGF suppresses, while Norrin-bCatenin promotes, the expression of the obligate endothelial heme importer, Flvcr2. Based on these data, we hypothesize that heme, is involved in retinal angiogenesis and retinal vasculopathies. The Specific Aims of this proposal are to (1) determine how heme intersects with Notch signaling to control angiogenic tip/stalk selection, (2) characterize the role for Flvcr2/heme in VEGF-induced angiogenic proliferation and neo-vascularization, and (3) determine whether induction of Flvcr2/heme signaling is sufficient and necessary to reverse the vascular defects and downstream vision changes observed in mouse models of exudative vitreoretinopathy. To accomplish these aims, we developed new tools to directly manipulate heme in cultured retinal endothelial cells and assess heme transport and intracellular trafficking in vitro. We also generated new conditional knock-in and knock-out alleles to manipulate endothelial heme transport in vivo. Our studies will fundamentally impact our understanding of how endothelial heme levels are controlled, and the role of heme in retinal angiogenesis and vascular disease.

The proposal focuses on understanding the neuro-vascular aging mechanisms associated with alterations in fetal growth by intrauterine hypoxia using molecular biology and physiology as an area. The aim of the study is to demonstrate that impaired fetal growth conditions are associated with epigenetic programming of aging-related DNA methylation, chromatin remodeling, and miRNA-omic profile of junctional complex genes in the neuroendothelium, which can alter BBB integrity and permeability, increasing cerebral damage which impacts the juvenile and adulthood neurocognitive function.

EFECTO DE LA OBESIDAD INDUCIDA POR EL CONSUMO DE UNA DIETA ALTA EN GRASAS SOBRE LA ACTIVACIÓN DEL INFLAMASOMA NLRP3 EN LA CÓCLEA Y LA FUNCIÓN DEL SISTEMA AUDITIVO

Estudio de casos de Diabetes Mellitus de nueva aparición

Polycystic ovary syndrome (PCOS) is a prevalent and multifactorial endocrine disorder in women, which is characterized by reproductive and metabolic alterations that include hyperandrogenism, polycystic ovarian morphology, anovulation, insulin resistance, dyslipidemia and obesity with a high risk to develop type 2 diabetes and cardiovascular disease. However, the mechanisms that contribute to the development of metabolic abnormalities are not completely understood. Currently, DNA methylation, an epigenetic mechanism that regulates gene expression, has been proposed as an attractive possibility that might explain the heterogeneity of the syndrome linking the effect of environmental factors on susceptible genes to the presence of metabolic features. Data from women with PCOS and animal models of hyperandrogenism have found differential methylation patterns in several gene promoters related to glucose and lipid metabolism leading to a dysregulation of the expression of these genes and metabolic disorders. On the other hand, several environmental factors that may contribute with the establishment of these epigenetic modifications in women with PCOS remain unidentified. In this regard, it is widely accepted that different foods and nutrients have an impact on the regulation of epigenetic mechanisms, among them it has been proposed that elevated folic acid (FA) levels could induce an hypermethylation of the DNA which could reduce the expression of important regulatory genes including those asociated with metabolic function. Interestingly, women with PCOS show changes in folate and homocysteine levels suggesting an altered folate metabolism, which could be associated to changes in the methylation patterns of metabolic genes. In the present research project, we propose that androgen excess disrupts the folate cycle leading to folate excess in women with PCOS compared to control women. This alteration leads to hypermethylation of candidate genes involved in glucose and lipid metabolism (PPARG, FOXO1, GPAM and APOA2) which may impact the metabolic phenotype of women with PCOS. To test this hypothesis, 37 women with PCOS and 37 control women will be recruited to assess the effect of androgen excess in women with PCOS on folate metabolism circulating biomarkers such as folates, vit B12 and homocysteine (Hcy) (Specific aim 1). These results will be categorized according to quartiles of folate consumption according to the dietary pattern, using a validated food frequency questionnaire, and associated with circulating androgen levels. In addition, to evaluate whether androgen excess induces changes in folate cycle enzymes, gene expression analyses will be performed in peripheral blood mononuclear cells (PBMC) (Specific aim 2). To establish the causality of our hypothesis, we will evaluate the effect of androgen excess on the folate cycle using a cellular model. For this, gene and protein expression of the enzymes involved on the folate cycle (MAT, SAHH, MS, MTHFR, FOL1R y AHCY) will be analyzed in an hepatocyte cell line stimulated with testosterone (Specific aim 3). To check the specificity of androgen action we will use androgen blockers and aromatase inhibitors. Finally, to determine the effect on genes associated to glucose and lipid metabolism, DNA methylation in promoter regions and gene expression of candidate genes associated to glucose and lipid metabolism (PPARG, FOXO1, GPAM and APOA2) will be analyzed (Specific aim 4). We expect to find an increase in folate and homocysteine levels, and decreased levels of vitamin B12 in women with PCOS, asociated with a decreased expression of folate metabolism enzymes. On the other hand, in the in vitro model, we expect high levels of folic acid and a decrease in the expression of genes involved in folate metabolism in hepatocytes stimulated with androgens. This dysregulation in folate metabolism induced by androgen excess may result in hypermethylation of genes involved in lipid and glucose metabolism such as PPARG, FOXO1, GPAM and APOA2, leading to a lower gene expression which may impact the metabolic parameters of PCOS women. The results obtained from this proposal will help to identify new mechanisms involved in the pathophysiology of metabolic alterations in PCOS leading to the development of more effective strategies of prevention and therapy

La contaminación ambiental extradomiciliaria es un importante problema de salud ambiental ya que es responsable del 7,6% de la mortalidad anual total y de la pérdida de 103,1 millones de años de vida saludable. Entre algunos de los efectos adversos que se han reportado para el Material Particulado, uno de los principales contaminantes, se encuentran aumento en la mortalidad, morbilidad, muerte prematura, enfermedades cardiovasculares y respiratorias, cáncer de pulmón, impacto adverso en la actividad del sistema nervioso central que resulta en deterioro cognitivo, y efectos nocivos sobre el desarrollo fetal y el embarazo, afectando mayormente a grupos más vulnerables. Si bien, a nivel global, se cuentan con estrategias y criterios de monitoreo de calidad del aire para identificar la concentración de los contaminantes relacionados con la salud, es posible que estos no permitan analizar con mayor profundidad las diferencias en la distribución geográfica de los contaminantes y su impacto en poblaciones específicas. En ese sentido, el presente proyecto tiene el objetivo de establecer una metodología para la generación de un mapa confiable de la contaminación del aire a partir de una red de monitoreo, el cual permita correlacionar de manera más precisa a través de modelos de interpolación, la contaminación del aire con los problemas de salud respiratorio de las personas del sector considerado, hacer una validación de la metodología propuesta con un programa piloto en un área a determinar de la comuna de Rancagua y realizar divulgación de resultados en colegios y jardines de la región con la finalidad de generar un debate más amplio y democrático sobre tanto de prácticas personales así como de las nuevas políticas relacionadas con la contaminación del aire. Para esto se propone emplear diversos métodos propios de cada disciplina. Primeramente, se estimará un radio máximo de cobertura de un sensor dentro del cual se garantice cierto grado de confianza (Variograma empírico) respecto de los valores entregados por el sensor como promedios representativos, para así determinar el tamaño/forma del área geográfica total donde instalar la red de sensores (Obj 1). Con esta información se determinará una configuración inicial de los sensores en un área geográfica determinada considerando la capacidad de la red, usando como ubicación potencial establecimientos educativos. Luego se hará un análisis estadístico con los datos proporcionados por la red y por sensores móviles para determinar una nueva configuración que maximice la confianza de la nueva interpolación. Una vez instalados los sensores y a partir de los datos entregados por ellos se escogerá una nueva configuración a través de un análisis estadístico de covarianzas (Obj 2). Además, se realizará un estudio ecológico para correlacionar las mediciones de contaminación de aire y algunos indicadores de salud respiratoria y atención de salud considerando distintos puntos geográficos de la sexta región (Obj 3). Finalmente, el proyecto desarrollará un plan de educación ambiental para concientizar sobre el tema y favorecer el cambio de comportamientos a nivel individual y comunitario (Obj 4). Con este proyecto se espera abordar con una visión interdisciplinaria un tema que es de especial preocupación en la región, como es la contaminación ambiental, fortaleciendo esta línea de investigación tanto en el instituto de ingeniería como en el de Salud, involucrando de forma activa también a estudiantes de pregrado.

Consolidar y fortalecer una nueva red de nodos de innovación social que promueva la inclusión socio laboral en personas con alguna discapacidad, personas mayores, mujeres y personas en situación de vulnerabilidad enfocada en los sectores económicos priorizados en la Estrategia de Desarrollo Regional 2011-2020 (EDRE) y de innovación, priorizando el sector turístico, y agroalimentario y la puesta en valor de la identidad cultural.

Antimicrobial resistance is a global phenomenon aggravated in recent decades by the inappropriate use of antimicrobials in human and veterinary medicine, the lack of prevention and control measures for infections associated with health care, and the limited development of new antimicrobials. It causes an increase in mortality, morbidity, and health spending. In this sense, the irrational use of antimicrobials in food-producing animals can reduce the effectiveness of those antibiotics in treating animal and human diseases. It also represents an additional risk for antimicrobial resistance by transferring antibiotics to food for human consumption and generating a new source of exposure. The residual antibiotics in food have been related to some adverse effects on human health, including allergic reactions, disruption of digestive system function, and chronic toxic effects from prolonged low-level exposure. It also represents a risk for the animals by jeopardizing the effectiveness of the necessary treatments. Considering that, the project seeks to generate evidence regarding progress at the local level in regulatory issues and regarding the presence of antibiotics in food to raise awareness about the proper use of antibiotics in animals and humans and promote good practices

Water is an irreplaceable resource for developing socioeconomic activities and maintaining life on the planet. According to projections, water scarcity will increase, especially in those countries vulnerable to the effects of climate change and accelerated population growth. The negative impacts of the water deficit are already visible in some regions of the planet. Through the ECOH-WATER project, we will develop capacities for the access and use of rainwater in educational centers in Guatemala and Bolivia for sustainable consumption, adapting to the impacts generated by climate change through strategies based on local needs. To do this, we will first diagnose the areas at risk of drought using Geographic Information Systems (GIS) to prioritize interventions. In the selected areas, we will develop an Action Research study with a strong participatory component to involve communities in implementing a rainwater harvesting system. Additionally, we will implement educational strategies for developing skills in seeking rational and sustainable water use. The project will establish alliances with local actors for the project's sustainability. The search for strategies to access quality water for human, animal, and environmental consumption is a worldwide priority. It must involve the communities, raise awareness about natural resources and risk behaviors, and work collaboratively with decision-makers. On the other hand, the transdisciplinary work proposed in this project will allow the search for solutions with an integral vision. On the other hand, this project highlights the south-south collaboration to generate learning, enhance local resources, and move toward our region's sustainable development.

The environment can be described as indispensable as it houses all life on earth, and evidence suggests that activities in interaction with nature not only provide physical and psychological benefits but also socially and economically. Nonetheless, we are currently confronted with many environmental challenges, including climate change, loss of biodiversity and degradation of natural habitats, which have adverse health outcomes for animals, humans and our shared environment. Furthermore, regarding the COVID-19 pandemic, additional threats have emerged such as an increase in the use and disposal of plastic products for medical and non-medical applications and the amount of packaging used to deliver food and groceries to residences, leading to significant challenges in handling solid and hazardous medical wastes. This could become a crucial concern in the medium or long term, whilst aggravating the already existing issues, especially in countries with inadequate waste management systems. Recognizing this, environmental education has become more relevant than ever in ensuring a sustainable future by promoting responsible decision-making at the individual, institutional and community levels. The strengthening of environmental literacy through formal and informal educational strategies at different stages of the life course, considering day-to-day situations, will eventually allow for the development of capacities in the population, thereby conserving our shared environment. Project aim: The project's main objective, therefore, is to empower the community for environmental care through educational strategies based on local needs in Guatemala and Bolivia. This is to be achieved using a Participatory Action Research (PAR) approach by forming a multidisciplinary and intersectoral working group that includes professionals from the academy and representatives from diverse sectors like education, work, transportation, legislators and civil society. The project also follows a spiral approach, focusing on a problem and continuing with planning, action, observation and critical reflection, giving rise to a new progressive cycle. To better disseminate the project and population adherence, a digital platform app is to be designed to make available all the education material and specific guides that support this process. Ultimately, creating awareness and educating, based on evidence, about our actions' impact will allow a better co-existence and promote sustainable development, sustainable use and care of natural resources when considering practices in rural and urban communities