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.

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.

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.

Hay pruebas sólidas de que tanto la restricción del crecimiento intrauterino (RCIU) y la macrosomía fetal (peso
al nacer > 4000 g) están fuertemente asociados con el aumento del riesgo de enfermedades crónicas en la vida
adulta (i.e. hipertensión arterial y diabetes tipo 2). La asociación entre el desarrollo peri-concepcional y fetal con
la salud en la vida adulta, llamada “Programación Fetal” se basa en la activación de mecanismos de detección
y señalización de una diversidad de estímulos durante el desarrollo temprano. Los mecanismos que han sido
ampliamente sugerido que participan en estos procesos son las modificaciones epigenéticas que podrían
registrar los estímulos perinatales. Como testigo de los cambios perinatales a los que se ve expuesto el
embrión y luego el feto en su desarrollo y crecimiento está la placenta, que junto con estar constituida por tejido
que regula el intercambio de nutrientes y la modulación inmune está formada por una importante red vascular
que permite obtener desde la sangre materna los nutrientes, el oxígeno, las señales hormonales y del sistema
inmune. El sistema vascular de la placenta se proyecta igualmente en la circulación sistémica del feto, donde se
sugiere que ocurren adaptaciones en las condiciones patológicas antes mencionadas (RCIU y macrosomía fetal
secundaria a obesidad materna), condicionando así a estos niños a presentar un elevado riesgo de
enfermedades cardiometabólicas en la vida adulta.
Este proyecto propuso estudiar la presencia de marcas epigenéticas (cambios en el patrón de metilación de
citosinas en la región promotora de genes y cambios en la modificación de histonas que participan en el estado
de compactación/relajación de la cromatina) en las células vasculares de la arteria umbilical (HUAEC), cambios
en la función vascular y expresión de genes, proteínas y actividad de enzimas claves en la función vascular en
tres grupos de gestantes: 1) gestantes normopeso con fetos de crecimiento normal denominados “Adecuados
para la Edad Gestacional” (AEG); 2) gestantes normopeso con fetos que presentaron Restricción del
Crecimiento IntraUterino (RCIU) y 3) gestantes con obesidad pregestacional que tuvieron hijos que fueron
Grandes para la Edad Gestacional (FMOM).
Los objetivos y los resultados principales de este proyecto fueron:
1) Estudiar el tono vascular de las arterias umbilicales y coriónicas de la placenta en estas tres condiciones
clínicas con acento en la participación de las vías dependiente de óxido nítrico, un vasodilatador dependiente
del endotelio, clave en el tono vascular placentario. Se determinó que las arterias coriónicas y placentarias de
los fetos RCIU y FMOM presentan disfunción vascular dependiente de óxido nítrico y que existe un desbalance
entre la actividad de arginasa-2/eNOS que favorece esta disfunción. (ver Krause et al. Placenta 2012; 2013;
Schneider et al., Placenta 2015).
2) Determinar si estos cambios en el tono vascular placentario y umbilical se correlacionan a cambios en la
expresión de genes y proteínas claves en la función vascular (eNOS, Arg2, CAT-1) y de respuesta estrés
oxidativo (NOX4, GPx-1, SOD-1 y HO-1) en los cultivos primarios de HUAEC de las tres condiciones clínicas,
así como en los tejidos (cordones umbilicales y arterias coriónicas) (ver Schneider et al., Placenta 2015). Se
determinó que estos vasos están marcados por una respuesta crónica a estrés oxidativo, presentando una
limitada reserva vascular al estrés oxidativo, comparado con los tejidos provenientes de embarazos AEG (ver
Schneider et al., Placenta 2015).
3) Estudiar la presencia de modificaciones epigenéticas presentes en la región promotora de los genes
relacionados con la vía de síntesis del óxido nítrico (NO) y determinar si la respuesta al estrés oxidativo y/o
hipoxia están programadas epigeneticamente. Se determinó que de todos los genes estudiados sólo eNOS y
Arg2 presentan cambios en el patrón de metilación en la región promotora (ver Krause et al., Epigenetics
2013) que se correlacionan con las modificaciones de histonas encargadas de regular el estado de
compactación de la cromatina (Caniuguir et al., en preparación).
4) Ahondar en la participación de los mecanismos epigenéticos (HDAC y DNMT) en la expresión basal de estos
genes en las tres condiciones clínicas. Se determinó muy elegantemente como NO es quien regula a nivel
epigenético la apertura de la cromatina de arginasa 2 y su actividad transcripcional (ver Krause et al., Biochem
Pharmacol 2016).
El desarrollo de este proyecto tuvo como fruto 18 artículos en revistas indexadas, la mitad de ellos
directamente relacionados con resultados de este proyecto y los otros de colaboraciones nacidas durante estos
años, que apuntan directamente a comprender los mecanismos que subyacen la programación fetal de
enfermedades cardiometabólicas en tejido placentario, en niños pre-adolescentes, modelos animales de RCIU y
obesidad materna, proyectos clínicos de seguimiento de niños, etc.
Este proyecto aportó en forma sustantiva a la generación de nuevo conocimiento en relación a los
mecanismos moleculares que subyacen a la programación vascular alterada en fetos con RCIU y FMOM,
que están en mayor riesgo de desarrollar enfermedades vasculares en la vida postnatal, con la relevancia
clínica de la potencial aplicación en la detección temprana de factores de riesgo cardiovascular en el
nacimiento.

Compelling evidence shows that adverse intrauterine conditions 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 lead 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 is a common feature in conditions with altered fetal growth (i.e. intrauterine growth restriction –IUGR-, or macrosomia). Several cellular processes require the participation of pro-oxidant molecules which are normally neutralized by antioxidant defenses. However, under determined conditions 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).
Interestingly, cultured placental endothelium derived from complicated pregnancies presents persistent abnormal phenotypes, characterized by altered expression of proteins involved in NO-dependent vasodilation (i.e. eNOS and arginase), suggesting an early onset of endothelial dysfunction. Preliminary data from in vitro experiments, show that this altered expression of eNOS in IUGR placenta-derived endothelial cells is accompanied by epigenetic alterations in the promoter of its gene. Moreover, these cells can be reprogrammed to a “normal type”, interfering with the molecular machinery that preserves the DNA methylation pattern. However, there are no studies addressing the role of the pro-oxidant status associated to IUGR on the epigenetic programming of placental vascular dysfunction, and whether these epigenetic changes reflect those present in other fetal vascular beds or in the adult cardiovascular system.
Therefore, we hypothesized that the in utero oxidative stress, that characterizes IUGR, induces an epigenetic programming of the endothelial function, which is linked to abnormal umbilical and fetal vascular reactivity and higher risk of adult cardiovascular disease. These epigenetic changes lead to an altered expression of endothelial function-related proteins and to their response to superimposed oxidative stress in umbilical and systemic arteries in the fetus and adult guinea pig.
If true, the development of IUGR in the presence of antioxidant treatment should prevent the vascular impairment in the fetus and the adult guinea pig. This hypothesis will be tested in an IUGR guinea pig model according to the following general aims (GA): GA-1. To determine whether the IUGR-associated oxidative stress induces endothelial dysfunction in umbilical and systemic arteries, altering the basal expression of proteins implicated in the NO-dependent vasodilation (NO-DV) pathway and their response to oxidative stress; GA-2. To determine in umbilical artery (UAEC) and aortic (AEC) endothelial cells whether endothelial dysfunction induced by fetal oxidative stress associates with epigenetic changes in the promoter of genes implicated in the NO-DV pathway, altering their response to oxidative stress in vitro; GA-3. To determine in adult life whether the IUGR-associated oxidative stress results in increased markers of endothelial dysfunction, oxidative stress and cardiovascular disease. GA-4. To determine in AEC of adults born with IUGR whether endothelial dysfunction induced by fetal oxidative stress is associated with epigenetic changes in the promoter of genes implicated in the NO-DV pathway and their response to oxidative stress in vitro, correlating them with those found at term of gestation.
IUGR will be induced by uterine artery ligation in a pregnant sow, and the role of oxidative stress in the vascular programming will be analyzed treating IUGR pregnancies with the antioxidant N-acetylcysteine. The acute effect of pro- and anti-oxidants on vascular reactivity and NO-dependent vasodilation will be determined by wire-myography in IUGR near-term fetuses and adults guinea pig arteries. Further, the presence of proteins related with NO-dependent vasodilation (eNOS, arginase, HO-1, NQO1 and DHFR) in these vessels will be determined by immunohistochemistry. Endothelial epigenetic programming will be analyzed in primary cell cultures from UAEC and AEC in near-term fetuses and AEC in adult guinea pigs.
Our expected outcome is to demonstrate that oxidative stress is one of the main sources of the IUGR-induced dysfunction in fetal and adult vascular beds. Further, we expect that the NAC treatment should be able to prevent partially or totally the programmed vascular impairment. This project is not only relevant to uncover the developmental mechanisms that determine short- and long-term vascular dysfunction, but also to propose eventual treatments in complicated pregnancies, that unfortunately present a very high rate in humans.

1. La hipertensión arterial esencial es el principal factor de riesgo cardiovascular, con una prevalencia del 30-40 % en la población adulta, que llega al 75% en mayores de 65 años. A pesar del desarrollo de fármacos, la efectividad de los tratamientos actuales es limitada. En cerca de 50% de los pacientes, el tratamiento farmacológico no logra controlar la presión arterial elevada. La hipertensión es de origen multifactorial, pero existe consenso que la disfunción endotelial juega un papel primordial en su desarrollo. La bio-disponibilidad del óxido nítrico (NO), que es el principal vasodilatador, está reducida en la mayoría de las enfermedades vasculares debido al estrés oxidativo y al aumento de la expresión y actividad de arginasa, una enzima que compite por el sustrato del NO. Este proyecto desarrollamos una nueva combinación farmacológica dirigida a proteger el NO, combinando las propiedades vasodilatadoras y anti-remodeladoras del inhibidor de la arginasa ácido 2(s)-Amino-6-Boronohexanoico (ABH) y de del antioxidante N-Acetilcisteína (NAC). Buscamos introducir una nueva forma de enfocar el tratamiento para la hipertensión arterial, atacando con esta formulación farmacológica los mecanismos moleculares que subyacen a la disfunción endotelial: baja bio-disponibilidad de NO y aumento del estrés oxidativo. En un modelo de hipertensión en ratas inducido por hipoxia intermitente crónica, cuya presión fue monitorizada por telemetría, evaluamos el efecto de la combinación sobre la hipertensión arterial y la disfunción vascular. La combinación ABH+NAC reduce la presión arterial elevada, revierte la reducción del diámetro interno de las arterias, regulariza la función endotelial y contráctil en arterias y disminuye el estrés oxidativo. No encontramos efectos adversos sobre la función renal y hepática. Estos resultados dieron origen a la presentación de dos solicitudes de patentes en Chile y de protección CTP en el extranjero para un nuevo método de síntesis de ABH y de los efectos benéficos de la combinación sobre la hipertensión y disfunción endotelial. En conjunto con el Laboratorio Andrómaco se estableció una estrategia de propiedad industrial ex post, así como las acciones científico-tecnológicas conducentes a las siguientes fases de desarrollo del medicamento: pruebas preclínicas en otros modelos de hipertensión, desarrollo galénico y/o fase clínica I. Dado que el resultado de producción de la formulación deberá pasar aún por pruebas clínicas antes de ser dispuesto a los beneficiarios, la patente de este nuevo fármaco podrá ser utilizada como activo principal para capturar capital de inversión que permita continuar con este proceso, o bien para licenciar a empresas con interés en el rubro. Junto a la Fundación del Adulto Mayor, desarrollamos actividades de extensión con la finalidad de informar a la comunidad y con ello contribuir a prevenir los efectos deletéreos de la hipertensión en la población de mayor riesgo cardiovascular. En esta propuesta se espera validar una nueva terapia antihipertensiva que ataque los mecanismos fisiopatológicos principales de la disfunción vascular que conduce a la hipertensión arterial esencial.

Asthma is a chronic disease that affects young children starting mostly in the first years of life; with a high prevalence across countries globally. In Santiago, Chile, the prevalence of asthma among children 6-7 and 13-14 years of age is 11% and 15%, respectively; and for recurrent wheezing during the first year of life is as high as 22%. Asthma is the fourth most common cause of disability-adjusted life years for children aged 10–14 yrs and an important cause of reduced quality of life and exercise tolerance, higher rates of school absenteeism and hospitalization. A recent study done in Santiago reports that 30.4% of all infants visits to the emergency department presented with wheezing and wheezing exacerbations accounted for 8.4% hospital admission. Treatment of asthma currently focuses in reducing symptoms; however the morbidity remains high due to limited curative options and the unresolved etiology of asthma. There are no well-established methods or diagnostic tools to indentify the risk to develop asthma, and the current accepted practice base the diagnosis on parental or self-reported symptoms. One of the most accepted tools to predict asthma early in the infancy was developed by our team (the Asthma Predictive Index); and has been incorporated in most asthma early diagnosis guidelines globally. However, there is growing evidence supporting that beside genetic inheritance, maternal health during gestation represents an important factor conditioning the risk of asthma in the offspring. Thus a better understanding of pathogenesis of asthma in the neonatal period throughout uncovering the mechanisms that explain the associations between fetal life cues with asthma would contribute to an early prevention and treatment.
Immune function plays a central role in the development of asthma, but the relative contribution of different immune cell types (i.e. mast cells, eosinophils, lymphocytes, neutrophils and monocytes/macrophages) to this disease is still under examination. Nonetheless, it is clear that asthma presents an altered expression of pro-inflammatory molecules (IL-12, TNF-α) and anti-inflammatory mediators (IL-10, IL-4). Notably, modulation of M1-M2 polarization of monocytes and macrophages seems to be crucial for the development of altered immune response in asthma, and this process would be tightly regulated by epigenetic mechanisms (i.e. DNA methylation, histone modifications). Numerous clinical and epidemiological studies have underlined the detrimental or beneficial role of nutritional factors in complex inflammation-related disorders such as allergy and asthma. It is now progressively better established that most of this risk is influenced in the very early stages of development, by a process of “early life programming” in which epigenetic mechanisms will actively participates. Remarkably, maternal obesity during gestation associates with increased plasma levels of TNF-α at birth, and a 4-fold increased risk of asthma in the offspring. Also growing data show that epigenetic mechanisms exert an important control on the altered immune function observed in autoimmune and inflammatory controlling the expression of key genes. However, whether maternal obesity during pregnancy influences the immune function and the risk of asthma in the offspring throughout epigenetic mechanisms has not been addressed.
In this context we propose that “Maternal obesity during pregnancy increases the risk of developing asthma in the offspring by an epigenetic-mediated programming of the inflammatory response in monocytes. This programmed inflammatory response is characterized by a higher expression of pro-inflammatory molecules (IL-12, TNF-α) along with a lower expression of anti-inflammatory mediators (IL-10, IL-4Rα) which occurs due to changes in the methylation status of the promoter regions of these immune response- key genes”. Studying a cohort of 400 children (0–3 years old) born from mother with or without obesity during pregnancy this proposal will address whether: a) the increased risk of asthma in children born from obese mother can be observed at 3 years of life; b) the increased asthma risk in these children associates with an altered immune reactivity in monocytes at birth; and c) the altered immune reactivity in monocytes occurs along with changes in the DNA methylation status at the promoter regions of asthma-related genes.
This study would reveal new molecular markers contributing to early diagnosis of asthma during childhood, as well as establish the real effects of epigenetic mechanisms modeling the immune function and responses at long term.

Overweight and Obesity are worldwide epidemic conditions defined as a body mass index (BMI) ≥ 25 and ≥30, respectively, characterized by an excessive accumulation of adipose tissue in the body that impairs both physical and psychosocial health and well-being [1]. Notably, according to the Chilean National Health Survey (ENS 2009-2010), 60% of woman in reproductive age (i.e. 15 and 44 years) are overweight or obese [2] with detrimental consequences on women as well as offspring health at long term. Epidemiological evidences have recognized pre-gestational obesity and, in a lesser degree, excessive gestational weight gain (GWG) as independent risk factors in the development of maternal complications and adverse perinatal outcomes [3]. This includes congenital malformations, perinatal death, large for gestational age babies (LGA, >p 90th), macrosomia (> 4 Kg at birth), birth dystocia, neonatal hypoglycemia, and others [4]. This evidences leaded the Institute of Medicine of the National Academy of Sciences of the United States (IOM) to provide guidelines for maternal weight gain in 1990, updated in 2009 [5] in order to improve maternal and perinatal outcomes. Conversely, a large number of evidence has shown that a deficient maternal nutrition during pregnancy affects the early in utero development, inducing adaptations/responses in the fetus and neonate which have been associated to increased risk of diseases in adulthood [6]. This concept, known as “Developmental Origins of Health and Disease” (DOHaD, referred also as intrauterine programming in this proposal) which was coined by Professor David Barker, who reported the association of low birth weight and the risk of T2DM and cardiovascular disease. Notably not only in utero under-nutrition (e.g. intrauterine growth restriction) but also over-nutrition (e.g. macrosomia, LGA) increase the cardiometabolic risk in the offspring [7-9]. Whilst the effect of maternal undernutrition on the risk of disease in the offspring has been extensively addressed, new efforts are required to clarify how increased maternal obesity and body fat previous and during pregnancy impinge an increased cardiometabolic risk in the progeny.
In this context, in addition to perinatal complications associated with maternal obesity (MO), there is evidence of persistent adverse effects in the offspring throughout their lifespan. In fact, excessive maternal gestational weight gain is associated with a 2-fold increase in cardiometabolic risk in the offspring, which is evidenced since early infancy [10]. Notably, this effect is substantially higher (~5-fold increase) in offspring from women that initiate their pregnancy with obesity [11, 12]. This is relevant due to the high rate of childhood overweight/obesity in Chile (32.2% of the children ≤ 6 yo are overweight/obese, according to the ENS 2010), which is a strong predictor of later cardiometabolic complications in adulthood [13]. The effect of MO on susceptibility to obesity in the offspring appears to be independent of the presence of gestational diabetes (GDM) [14, 15]. This could have its origin during fetal development since it has been described that newborn whose mothers are obese, with normal glycaemia during gestation, present an increased adiposity versus lean mass compared to control pregnancies [16]. In this respect, it is noteworthy that the size of abdominal adipose tissue and hepatocellular lipid content in neonates strongly correlates with maternal BMI [17-19]. This has been also observed in offspring from pregnant obese non-human primates and mice, which exhibit increased accumulation of hepatic triglycerides and ceramides even before birth [17-19]. Furthermore, MO also relates with metabolic disturbances in the newborn, such as a reduced insulin sensitivity and altered inflammatory markers [20]. Altogether these data suggest that postnatal obesity could be programmed by MO during fetal development, however the mechanisms underlying the intrauterine programming of obesity are currently unknown. In this context inflammation, a mechanism exacerbated in pregnancies with MO, represents a potential pathway participating in this process.