Proyectos

During the last decades, compelling evidence shows how the context in which early life takes place impinges risk or protection for later development of non-communicable chronic diseases. In this regard, impaired fetal growth, as occur in the fetal growth restriction (FGR), leads to a higher risk for later cardiovascular diseases, an effect that would be mediated by accelerated aging at molecular, structural, and functional levels. FGR remains a leading cause of perinatal morbidity and mortality, affecting ~10% of pregnancies, but ranging 5 to 25% depending on the nutritional and health conditions of the population surveyed, with a higher prevalence among pregnant women of low socioeconomic status. In the clinic, FGR is normally defined by a fetal weight below the 10th percentile, however, new evidence shows that impaired intrauterine growth may affect several neonates born over the 10th percentile, which may be missed from the perinatal survey for preventing adverse outcomes. This points out the need for further studies to improve the understanding and identification of altered fetal growth trajectories and their consequences on vascular function. Studies in placenta show that FGR vascular dysfunction is also found at birth in chorionic and umbilical arteries. We have demonstrated the presence of functional and molecular markers (e.g. epigenetic changes) of endothelial dysfunction in human umbilical and chorionic vessels, findings that have been further confirmed by comparing systemic (aorta and femoral arteries) and umbilical arteries in animal models of FGR. These traits suggest that umbilical artery endothelial cells (HUAEC) can be used as a surrogate to explore the vascular programming within the fetus, however, their translation to clinical preventive applications for promoting healthy aging deserves further studies. It worth noting that fetal reduced oxygen supply (i.e. fetal hypoxia) and altered blood flow patterns (i.e. shear stress) are key clinical markers in the FGR, independently of the constraints leading to impaired growth, and both factors exert a tight control of vascular development and function across life. However, how these key stimuli interact and impose an epigenetic program on the endothelial function remains elusive. This proposal will focus on the crosstalk between hypoxia and shear stress that results in the endothelial programming related to impaired fetal growth, and the molecular mechanisms that mediate the vascular responses to these stimuli. Furthermore, we will address if these molecular markers may allow detecting early vascular aging in FGR subjects beyond the 10th centile cutoff. We hypothesize that “Impaired fetal growth conditions are associated with epigenetic programming of aging- and mechanosensing-related miRNAs and transcripts in the endothelium, which can be triggered by the confluence of altered flow patterns and hypoxia resulting in molecular and structural pro-hypertensive biomechanical vascular properties”. This hypothesis will be addressed by three General Objectives (GO) involving ex vivo, in vitro, and in vivo observational and mechanistic approaches: GO1 To demonstrate, in HUAEC, whether late FGR results in epigenetic changes related to the regulation of vascular aging and the expression of mechanosensing mechanisms involved in the endothelial-dependent relaxation, and their relationship with general prenatal parameters of vascular health. GO1 will be performed by recruiting HUAEC samples from late FGR and control pregnancies, to assess transcriptomic and DNA methylation analyses that will be crossed with prenatal clinical data. GO2 To study, in vivo, whether stimuli related to FGR (i.e. hypoxia and altered shear stress) differentially regulate mechanosensing pathways involved in the endothelial-dependent relaxation and their relationship with the in vivo and ex vivo vascular properties (e.g. functional and biomechanical). GO2 will be performed in chicken embryos exposed to hypoxia and treated with agents targeting mechanosensing pathways, in which wall shear stress will be determined by Ultrasound Localization Microscopy, with complementary functional, structural, and molecular analyses. GO 3. To study, in cultured HUAEC, whether stimuli related to impaired fetal growth converge in the regulation of mechanosensing-and aging-related transcripts and miRNA, contributing to the cellular programming of endothelial dysfunction. OG3 will be performed in HUAEC exposed, in vitro, to sustained hypoxia and diverse flow patterns (shear stress), in which target DNA methylation, miRNA, transcripts, and proteins will be assessed. Our expected outcome is to improve the knowledge about the endothelial epigenetic programming after FGR and enhance the characterization of in vivo shear stress patterns and mechanisms induced by chronic fetal hypoxia. This project is not only relevant to uncover the developmental approaches for diagnosing and treatments in complicated pregnancies.

One goal is to enhance the methods being currently developed by Espı́ndola (Physics), Krause (Physiology), and Xavier (Biomedical Engineering) for reconstructing capillary networks with ultrasound. The super-resolution is needed for early detection diseases such as cognitive decline, cancer, or liver fibrosis. They perfuse lipid-encapsulated microbubbles as contrast agents and then localize the bubbles in the ultrasound images with the singular value filter. However, that method leaves a non-negligible percentage of bubbles undetected. Here we propose to complement the singular value filter for the detection and tracking of microbubbles with the sophisticated and mathematically sound Mumford-Shah method for image contour detection, which stems from the conceptually-insightful and numerically-robust perspective of the minimization of energies. In the reconstruction of the capillary network from ultrasound, it is impossible to directly distinguish the microbubbles, or even the blood vessels, in each frame separately, due to the attentuation and degradation in this imaging technique. It is essential to take into account the dynamic nature of the problem, distinguishing the slowly-varying signals emitted by the tissue from those emitted by the microbubbles, which flow rapidly, behave nonlinearly, and have a much shorter coherence length. We therefore propose to regard the collection of two-dimensional frames as a single three-dimensional image, where a moving bubble becomes a tubular neighbourhood of a filament, which the Mumford-Shah model is expected to recover. From these filaments, bubbles can be detected and tracked, and the vertical inclinations of theses filaments will yield the microbubbles velocities. From the velocity profiles it is possible to estimate the shear wall stresses (their ‘tangential elastic rigidities’) of the blood vessels, and anomalies in these stresses are commonly good indicators of the presence of specific diseases. A fortunate encounter between mathematics and mechanics led to the observation that the problem of finding the path that the propagation of a crack will follow inside a structure upon loading could be solved with the mathematical theory (the analysis of free-discontinuity problems) developed for the apparently unrelated image segmentation Mumford-Shah model. The variational fracture theory initiated by Francfort and Marigo is by now (20 years after) very well established. The second goal of this proposal is to further develop the ongoing collaboration between Song (Pharmaceutics), Siegel (Pharmaceutics), Sánchez (Numerical analysis), Calderer (Applied mathematics), and the PI on the study of the debonding of polymer gels from rigid substrates (relevant in the design of the synthetic polymers coating the metallic parts of pacemakers and other medical prostheses) from this variational fracture theory perspective. The third main goal is to apply the mathematical analysis of free-discontinuity problems to the modelling of the evolution of the cavity in the block caving technique in underground rock mining. This has been pursued by Ortega, Lecaros, and coworkers from the side of applied mathematics in academia, in collaboration with Gaete from the Geomechanics Research Department at El Teniente, research group to which Gutiérrez and the PI have joined in the last months. We propose to study the seismic activity induced by the fracture of the rock mass due to gravity, following the works in the last decade within the variational fracture theory that incorporate the inertia effects. The final aim is to optimize the injection of water jets for the aminoration of the seismic events near the operation sites. The three research lines are applications of the phase-field regularization by Ambrosio and Tortorelli of the Mumford-Shah free-discontinuity model, a different variant being required in each of the three contexts. The first stage of the implementation is of mathematical modelling and high-level numerical simulation abilities, in which the intuition and first-hand knowledge from the members of the research team that are experts in vascular function, ultrasound imaging, polymer chemistry, and mining geomechanics is translated into particular mathematical concepts and concrete computational methods. This is followed by a stage of calibration and validation, where the full interplay with experiments is required. The product of a robust and validated computational method will constitute then an advancement in the capabilities, available resources, and understanding in each of the applied disciplines.

El cáncer es una enfermedad genética compleja y mortal que afecta a un gran número de personas en Chile, con una alta tasa de mortalidad y un aumento constante en el número de casos. Ante esta realidad, es crucial implementar la Medicina de Precisión en el país para brindar un tratamiento personalizado y mejorar los resultados para los pacientes. El Centro UOH de BioIngeniería (CUBI) se propone liderar este avance, enfocándose en la región de O'Higgins, Chile. El CUBI busca crear mapas moleculares multiómicos de los cánceres prevalentes en la región, utilizando tecnologías de vanguardia y algoritmos avanzados. Esto permitirá comprender los perfiles genéticos y moleculares del cáncer, así como la heterogeneidad y evolución somática de los tumores chilenos. El equipo propuesto por CUBI, con su destacada capacidad de secuenciación genómica, procesamiento masivo de datos y experiencia en biología molecular y computacional, desempeñará un papel protagónico en el logro de estos objetivos. El CUBI se organiza en tres líneas de investigación principales. La primera línea se centra en las tecnologías genómicas para el mapeo de genotipos, fenotipos y evolución tumoral, dirigida por el Dr. Di Genova. Su objetivo es comprender los factores genéticos que contribuyen al cáncer, así como la variabilidad molecular y la evolución somática de los tumores chilenos. La segunda línea, liderada por el doctor Henao, se enfoca en las tecnologías de imagen para el mapeo y evaluación de fenotipos tumorales. Mediante el uso de imágenes histológicas y de ultrasonido, combinadas con la inteligencia artificial y modelos físico/matemáticos, se busca identificar patrones morfológicos y topológicos asociados a biomarcadores o procesos mutacionales específicos de los tumores. La tercera línea de investigación, liderada por el Dr. Krause, se centra en la utilización de modelos preclínicos para validar las relaciones fenotipo-genotipo desCUBIertas en las líneas de investigación anteriores y la creación de un biobanco regional. Esto permitirá realizar estudios moleculares, clínicos y epidemiológicos en la región de O'Higgins, fortaleciendo la base de conocimientos y facilitando la aplicación de los hallazgos en la práctica clínica. El CUBI cuenta con un equipo interdisciplinario de investigadores jóvenes, intermedios y senior, con líneas de investigación claras y bien definidas. Además, se ha establecido una sólida red nacional e internacional de colaboración con instituciones líderes en investigación del cáncer, como el IARC de Lyon, Francia, el ICR de Londres, UK y hospitales e instituciones en Chile. El CUBI busca posicionarse como un centro pionero en la investigación en medicina de precisión oncológica en Chile. Su objetivo principal es comprender y mapear la biología única de los pacientes chilenos/as con cáncer, con el fin de brindar tratamientos más efectivos y mejorar las oportunidades para la región. Con su infraestructura, equipo, red de colaboración y enfoque multidisciplinario, el CUBI tiene el potencial de generar un impacto significativo en la sociedad chilena al avanzar en la comprensión del cáncer y la implementación de estrategias de tratamiento personalizado. Proyectamos que la operación del CUBI tendrá un impacto positivo en la región y país en varios aspectos: 1. Mejorar la atención del cáncer: El CUBI permitirá una mejor comprensión de las características genéticas y moleculares de los tumores en la población regional y nacional. Esto conducirá a un diagnóstico más preciso, una estratificación más efectiva de los pacientes y una selección más precisa de los tratamientos. Como resultado, los pacientes recibirán terapias más efectivas, lo que mejorará sus resultados clínicos y su calidad de vida. 2. Avances científicos y tecnológicos: El centro promoverá el desarrollo y la aplicación de tecnologías de vanguardia y métodos de análisis de datos avanzados. Esto fomentará la investigación científica del cáncer y permitirá descubrir nuevas asociaciones genéticas y moleculares, así como identificar posibles blancos terapéuticos. Estos avances no solo beneficiarán a los pacientes de cáncer en Chile, sino que también contribuirán al conocimiento global en la lucha contra esta enfermedad. 3. Formación y educación: El centro brindará oportunidades de formación y capacitación para estudiantes, investigadores y profesionales de la salud interesados en la medicina de precisión en oncología. Esto fortalecerá la capacidad científica y clínica de la región, permitiendo la formación de especialistas altamente calificados en el diagnóstico y tratamiento del cáncer. 4. Impacto socioeconómico: La detección temprana, el tratamiento personalizado y la reducción de los efectos secundarios innecesarios pueden mejorar la eficiencia de los sistemas de salud y disminuir los costos asociados con el cáncer. Además, la generación de conocimiento científico y tecnológico puede impulsar la innovación y el desarrollo de la industria biotecnológica en la región, creando oportunidades económicas y empleo especializado. En resumen, el CUBI tiene el potencial de generar un impacto significativo en la sociedad regional al mejorar la atención médica, impulsar la investigación científica, fortalecer la capacitación y la colaboración, y tener repercusiones socioeconómicas positivas. Al comprender y abordar la complejidad biológica del cáncer en la población chilena, se allana el camino para una atención más efectiva y personalizada, y se brinda esperanza a los pacientes y sus familias en la lucha contra el cáncer.

Frailty is increasingly becoming an important public health challenge worldwide because it is associated with older age, and with adverse outcomes such as reduced quality of life, increased mortality rates, hospitalizations, falls, depression, and dementia. Frailty is defined as dynamic state affecting an individual who experiences losses in one or more domains of human functioning (physical, psychological, social) that are caused by the influence of a range of variables, and which increases the risk of adverse outcomes. This more integral conceptual definition promotes the collaboration of scientists, social and behavioral professionals as well as clinicians from diverse specialties. In this proposal an interdisciplinary group (Biochemistry, Geriatric, Occupational Therapist, Kinesiologist, social worker, bioengineer, statistician among others) aims to evaluate frailty in Chile with a biopsychosocial approach with the final purpose to identify and manage frailty while taking into consideration all the dimensions. Additionally, we aim to design a multidomain personalized person-base intervention for a healthy aging that can uncover a circulating microRNA biomarker panel that can allow an early-detection of frailty, leading to a new multidimensional geriatric assessment. We propose the following hypothesis: A personalized multidimensional training program reduces the frailty prevalence, increasing adherence and participation in the program among community-living older adults. This intervention will be paralleled by a distinctive miRNA profile reflecting the multiple domains of frailty, as well as improvements in diverse psychosocial traits.

During the past few decades average life expectancy has dramatically increased worldwide; specifically by 2050 the number of older adults will overcome the number of young people in Chile. This leads to a major challenge due to multiple chronic diseases highly prevalent in elderly. Aging process is defined as a series of time-dependent physiological changes that decrease reserve and functional capacity of skeletal muscle. Several studies have proposed that aging is caused by damage of macromolecules by reactive oxygen species (ROS) and decreased autophagy levels, a process that is essential for skeletal muscle regeneration, homeostasis and function. Exercise is a novel strategy used in elderly, which has shown to improve muscle mass, muscle function and decrease chronic diseases in old individuals. However, the molecular mechanisms and signaling pathways involved on the benefits of exercise in aged skeletal muscle are not completely clear. While exercise regulations of oxidative stress and autophagy have been studied separately, a direct interplay between exercise inducing autophagy via a ROS-dependent pathway has not yet been addressed in young or aged human skeletal muscle. Moreover, studies in human skeletal muscle examining the autophagy modulation after endurance exercise are limited and controversial. Although it is known that resting autophagy levels are decreased in aged skeletal muscle, the effects of acute exercise on skeletal muscle autophagy between young and older adults remain to be elucidated and could shed light on regulation of autophagy in humans. Additionally, it is also not known if a controlled exercise-training program can induce similar increases in autophagy levels in older adults. Recently, we have shown that the non-mitochondrial sources of ROS, NADPH oxidases 2 (NOX2), plays a major role in ROS production in skeletal muscle, both at rest and during contracting activity. Furthermore, our preliminary results show that NOX2 expression is increased during the aging process and strongly correlates with decreased autophagy levels detected in aged human skeletal muscle. Moreover, we also show that 12 weeks of endurance exercise training reduced the NOX2 levels in aged human muscle. We speculate that a decrease in NOX2 associated with a decrease in ROS levels in aged skeletal muscle induced by exercise training will improve aged muscle function by re-stablishing autophagy up to young skeletal muscle levels

La suplementación con proteínas es una de las principales recomendaciones ante la practica regular de ejercicio físico de resistencia (RT). En personas mayores, la necesidad de proteína se incrementa particularmente ante cambios fisiológicos y fisiopatológicos los que se asocian con la pérdida de la función y tejido muscular, por lo que su ingesta se hace de mayor relevancia en esta población. Los lácteos fermentados como el yogur, y en especial los con un contenido extra de proteína, han aumentado su popularidad y consumo en el mercado nacional. Su composición nutricional resulta de particular interés, dado su perfil de aminoácidos y en particular su alto contenido de Leucina, el que podría compararse con los clásico suplementos de proteína recomendados para la ganancia y recuperación muscular. Objetivo: Analizar el efecto en la composición corporal, perfil lipídico, condición fisica y funcionalidad muscular inducidas por ingesta de yogures altos en proteína versus proteína Whey junto un programa de resistencia muscular en personas mayores Hipótesis: La ingesta de yogures altos en proteína conllevará a iguales o mayores ganancias de masa muscular, condición fisica y funcionalidad que las obtenidas con la ingesta de proteínas Whey en conjunto a un entrenamiento de resistencia en personas mayores. Metodología: Se reclutarán 16 personas mayores (60-75 años), sanas y sin intolerancia a la lactosa para llevar a cabo 8 semanas de entrenamiento de resistencia (RT) muscular 3 veces por semana, los que de forma aleatoria serán suplementados con yogurt alto en proteínas (YPRT) o proteína Whey (WPRT). Al inicio y al término de la intervención se evaluará la composición corporal mediante DEXA, fuerza muscular, consumo máximo de oxígeno y perfil lipídico. Resultados Esperados: Se espera que el grupo YPRT logre incrementos similares o superiores en la fuerza muscular, masa libre de grasa, perfil lipídico y disminución de la masa grasa y que el grupo WPRT.

Es proyecto busca comparar los efectos de diversos programas de ejercicio físico en diversos parametros pronosticos en pacientes con EPOC severo

Frailty is increasingly becoming an important public health challenge worldwide because it is associated with older age, and with adverse outcomes such as reduced quality of life, increased mortality rates, hospitalizations, falls, depression, and dementia. Frailty is defined as dynamic state affecting an individual who experiences losses in one or more domains of human functioning (physical, psychological, social) that are caused by the influence of a range of variables, and which increases the risk of adverse outcomes. This more integral conceptual definition promotes the collaboration of scientists, social and behavioral professionals as well as clinicians from diverse specialties. In this proposal an interdisciplinary group (Biochemistry, Geriatric, Occupational Therapist, Kinesiologist, social worker, bioengineer, statistician among others) aims to evaluate frailty in Chile with a biopsychosocial approach with the final purpose to identify and manage frailty while taking into consideration all the dimensions. Additionally, we aim to design a multidomain personalized person-base intervention for a healthy aging that can uncover a circulating microRNA biomarker panel that can allow an early-detection of frailty, leading to a new multidimensional geriatric assessment. We propose the following hypothesis: A personalized multidimensional training program reduces the frailty prevalence, increasing adherence and participation in the program among community-living older adults. This intervention will be paralleled by a distinctive miRNA profile reflecting the multiple domains of frailty, as well as improvements in diverse psychosocial traits.