Lines of investigation

Principal investigator: Sergio Lavandero
Associate Researchers: Valentina Parra, Vinicius Maracaja, Zully Pedrozo, Mario Chiong, Alfredo Criollo
National Collaborators: Lorena García, Guillermo Díaz-Araya, Rodrigo Troncoso, Mariana Cifuentes, Roberto Bravo-Sagua, Jaime Riquelme
International partners: JA Hill, TG Gillette, D Cao, D Cao (UT Southwestern Medical Center, USA), H Li (Wuham University, China), D Westenbrink (University of Groningen, The Netherlands). ZV Wang (City of Hope Institute, Los Angeles).

Heart failure is a clinical syndrome caused by a structural and/or functional alteration of the heart that can result in a normal or reduced cardiac expenditure at rest or during stress. It represents the final phase of various cardiovascular and/or metabolic pathologies, including arterial hypertension, myocardial infarction, arrhythmias, diabetes, etc. Both its incidence and prevalence has increased in the elderly due to the increase in life expectancy in recent decades. Heart failure is considered "the epidemic of the new century" and an important challenge for public health, especially in countries with increasingly aging populations.

Cardiac work requires the generation of significant amounts of energy (ATP), which is provided by mitochondrial metabolism. In hearts with failure there is energy depletion, for which we have hypothesized that alterations in mitochondrial morphology and function and their interaction with other organelles are involved in the genesis and progression of heart failure either with reduced ejection fraction ( HFrEF) or preserved (HFpEF).

Our objectives are:

1. To assess the role of mitochondrial morphology and metabolism and mitochondrial-endoplasmic reticulum communication in cardiomyocytes and vascular smooth muscle cells in the genesis and progression of HFpEF and HFrEF.
2. To evaluate how inflammation regulates mitochondrial morphology and metabolism in the genesis and progression of HFpEF and HFrEF.
3. To investigate the signaling pathways that control metabolism and inflammation by cytokines, VCAM1, galectin-3, angiotensin- (1-9), insulin, and IGF-1 in HFpEF and HFrEF.
4. To evaluate the association of the cardiovascular health index, echocardiographic and inflammatory markers with the incidence of HFpEF and HFrEF in the Maule cohort.

Principal investigator: Pablo Castro
Associate Researchers: Luigi Gabrielli, María Paz Ocaranza, Hugo Verdejo
National Collaborators: Ramón Corbalán, Clara Quiroga
International partners: JA Hill & TG Gillette (UT Southwestern Medical Center, USA), D Westenbrink (University of Groningen, The Netherlands), Marta Sitges (Hospital Clinic, Barcelona, Spain).

Heart failure, the common final stage of several cardiovascular diseases, is a worldwide pandemic that affects 26 million people worldwide, most of whom are women. From a physiological point of view, heart failure is defined as the inability of the heart to withstand the cardiac output required to meet the metabolic demands of the body, in addition to increasing the filling pressure of the left ventricle. A standard way of classifying heart failure is according to the degree of deterioration of the ejection fraction of the left ventricle that defines three subtypes, namely heart failure with reduced ejection fraction (HFREF), heart rate with preserved ejection fraction (HFPEF) and the middle range ejection fraction (HFMREF). Most clinical studies have focused on HFREF, a subtype of more common insufficiency in men against whom most pharmacological therapies are directed. Conversely, HFPEF, the most prevalent form in women, is little known and specific pharmacological therapies are missing. Our hypothesis is that the clinical differences between patients of female and masculine cardiac insufficiency depend on the differences related to gender in the heart structure, the signage of MIRNA, metabolism and immunity.

Our specific objectives are:

1. To assess gender-related differences in inflammation and remodeling of the heart in patients with heart failure.
2. To determine sex-biased miRNA expression in heart failure patients and its relationship with heart remodeling, inflammation, and metabolism.
3. To assess gender-related changes in inflammation and early myocardial remodeling in the general population of the MAUCO cohort.
4. To evaluate the impact of estrogen modulation in a murine model of HFpEF.

Principal investigator: Andrew Quest
Associate Researchers: Lissette Leyton, Vicente Torres, Lorena Lobos
National Collaborators: Denise Bravo, Manuel Valenzuela, Miguel O’Ryan, Manuel Varas
International partners: V Perez (Linus Pauling Institute, USA), C Salomon (University Queensland, Australia), Pascal Schneider (University Lausanne, Switzerland), Wael el Rifai (University Miami, USA), Chris Abneter (NCI, USA), J Heinecke (U Washington, USA).

Gastric cancer is the main cause of cancer-related deaths in Chile and Helicobacter Pylori infection (HP), is highly prevalent in the country (around 70-80% of the population), is considered an important risk factor for development. The disease. Given our previous work with HP, focused on Gamma Glutamil Transpeptidase (GGT) and Ureasa, and our broad interest in the signaling activated by extracellular vesicles (EV) of different origin, we will focus here on the study of cell death induced by H. pylori and the pro-inflammatory signaling triggered by the soluble virulence factors Ggt and Ureasa bacterial vesicles of the outer membrane (OMV).

Our specific objectives are:

1. To determine how Hp gamma glutamyl transpeptidase alters protein kinase R (PKR) like ER kinase (PERK) to promote survivin loss and gastric cell death.
2. Determine whether the virulence factor Helicobacter pylori urease 1a induces hypoxia induced factor through activation of receptors of TLR2 / 4
3. To determine whether the loss of E-cadherin observed in patient samples can be attributed to Rab5-dependent endocytosis and / or DNA-methyl transferases-dependent E-cadherin silencing.
4. Demonstrate that the co-incubation of Helicobacter pylori with Porphyromonus gingivalis increases the virulence of Helicobacter pylori.

Principal investigator: Alejandro Corvalán
Associate Researchers: Gareth Owen
National Collaborators: Enrique Norero, Gonzalo Carrasco-Avino, Marcelo Andia, M Garrido (puc), am Ziegler (UDD), L Jara (UCH), g calaf (u tarapaca), u urzua (Uch) and other accdis groups.
International partners: W El-Rifai (University Miami, USA), L Carvajal-Carmona (UC-Davis, USA), C Rabkin (NCI, USA).

Although the incidence and mortality of gastric cancer have decreased in recent decades, it remains a world public health problem. Gastric cancer is the fifth most common cancer and the third cause of death related to cancer worldwide. In addition, gastric cancer has marked geographical variations with high mortality rates in the countries of Asia and Latin America and the lowest in the US., Canada and Australia. These geographical variations could be related to the role of genetic ancestry or ethnic ancestry in the incidence and prognosis of gastric cancer. In addition, coevolution the pathogens associated with gastric cancer (H. Pylori and Epstein-Barr virus, EBV) could also contribute to these geographical variations. In this complex and heterogeneous scenario, our proposal will expand our anterior epigenomic approach (DNA and micro -border methylation) to new and emerging aspects of gastric cancer.

Our specific objectives are:

1. Identify genetic variants in germline genes that target microRNA CDH1 found negative for mutations CDH1
2. To identify the epigenomic dysregulation associated with the synergistic effect between EBV oncoproteins and environmental factors in EBV-associated gastric cancer (EBVaGC).
3. To investigate the role of exosomes and miRNA in the metastatic spread of gastric cancer.
4. Predict response to treatment based on methylated cell-free DNA (cfDNA) biomarkers.

Laboratory of Dr. Alejandro Corvalán

Laboratory of Dr. Francisco Aguayo

Principal investigator: Catterina Ferreccio
Associate Researchers: Juan Carlos Araya, Sandra Cortés
National Collaborators: M. arrese (gastroenterology, UC), C. Vargas (Biostatistics, Usach), Araos (Infectologist, UDD), V. Maracaja (Bioinformatic, Uch), C. Foerster (Nutritional Epidemiology, U O'Higgins), H. Jumping (Environmental Chemical Engineer, UC), R. Verdugo (geneticist, U. talca), L. huidobro (Nutrition, UCM), V. van de Wyngard (Epidemiologist, UC), P. cook (nurso, mph, UC), A. Riquelme (gastroenterologist, UC), I. Castillo (Ph.D., UCM), Francisco Barrera (Hepatology, UC), UC) Daniel Cabrera (Hepatology, UC), JP. Arab (Hepatology, UC) Y G Valdivia (Epidemiologist, UC).
International partners: J Koshiol & A Hildesheim (NCI/USA), N Salama (Fred Hutchinson Cancer Research Center), M Levine (University of Maryland, USA), Christian Abnet & Constanza Camargo (NCI/NIH USA).

Chileans have the greatest mortality from gallbladder cancer worldwide; Until 2010, gallbladder cancer was the first cancer murderer among women. The survival of gallbladder cancer is very low, only the early stages benefit from surgery and, in addition, this pathology in Chile is associated with gallstones. The result of bile calculations is the abnormal metabolism of lipids associated with obesity and female hormones. Chileans have one of the highest prevalence rates of bile calculations reported, with a surprising sex differential. In Mauco, at the age of 35 to 44, women had a 5 -time prevalence of gallbladder disease than men (36% compared to 7%), the proportion of sexes was reduced to only 1.6 in the age of 65 (62 vs. 38%).

Our specific objectives are:

1. Identify the role of sex, Amerindian ancestry, and known genetic factors in the development of gallstones and their progression to precancerous lesions. Explore the interaction of genetic susceptibility with diet, chemicals (pesticides, mycotoxins), blood lipids, and sex hormones. Study GBD family groups.
2. Investigate elements of the causal chain from obesity to dyslipidemia, systemic inflammation, chronic cholecystitis, and precancerous lesions.
3. Study the microbial profile of people with a normal gallbladder, gallstones, and cholecystectomy. To explore the association of microbiome profiling with chronic H. pylori and S. typhi transport, diet, and ancestry.
4. Determine if removal of the gallbladder modifies the lipid profile and fat content of the liver. To explore whether these effects are associated with changes in the microbiome.
5. Identify the genetic and environmental factors common to GBD, diabetes, cardiovascular disease, and stroke.

Principal investigator: Marcelo Kogan
Associate Researchers: Soledad Bollo, Andrónico Neira, Felipe Oyarzún, Javier Morales
National Collaborators: Eyleen Araya, Natalia Hassan
International partners: E Giralt (Institut of Biomedical Research Barcelona, Spain), F Albericio (University of Barcelona, Spain), J Samitier (Institute of Bioengineering of Catalonia, IBEC, Barcelona), GA Rivas, (University of Córdova, Argentina), LJ Cruz (University of Leiden, The Netherlands).

This Nanomedicine research line has collaboration projects with the different ACCIS research lines. For the continuity plan, we will focus our research on Nanomedicine and Chemical and Pharmaceutical Sciences on the following topics: Improvement of the administration and stability of medicines for the treatment of cardiovascular diseases and cancer. Drug formulation is important for the development of successful therapies. In this context, the selective administration is important to reduce the side effects and the premature release of the drug of a drug medication should be avoided. In this sense, therapeutic efficacy should be improved by achieving a controlled space-time release of therapeutic payload through the use of drug administration systems that respond to external stimuli. On the other hand, formulations can improve the pharmaceutical characteristics of a medicine, such as half -life and solubility. With this in mind, we propose the following hypothesis: "The use of nanovehicles improves the supply of antitumor drugs and angiotensin- (1-9)."

Our specific objectives are:

1. Improve the administration of antitumor drugs and angiotensin- (1-9).
2. Use exosomes to target drugs to specific organs and tumors.
3. Conjugate nanostructures with molecules targeting heart tissue for selective drug delivery.
4. Detect ultrasensitive biomarkers specifically related to cancer or cardiovascular diseases.

Principal Researcher: Mariana Cifuentes

Chronic diseases associated with obesity such as type 2 diabetes, cardiovascular diseases and certain types of cancer are one of the main causes of morbidity and death in the world, and three out of four Chileans over 15 are in the category of overweight or obesity. These diseases are the result that the fatty tissue in obesity becomes dysfunctional, associated with a pro-inflammatory state.

However, not all people with obesity develop metabolic complications, which has led to the concept of "metabolically healthy obesity" (MHO). Although clinical differences between MHO and metabolically non -healthy obesity (MUO) have been described widely, cellular and molecular mechanisms involved in the establishment of these phenotypes are largely unknown.

Our goal is to know the mechanisms within adipose tissue and in their communication with other cells and organs, which make a person with obesity or not to have the aforementioned alterations. In particular, we are interested in inflammatory mechanisms, which are transversal to a large number of chronic diseases, as well as communication mechanisms between cells and organs mediated by extracellular vesicles.

Principal Researcher:Laura Andrea Huidobro

Type 2 diabetes mellitus (DM2) is a highly prevalent disease worldwide. According to national health surveys, in Chile, it increased from 6.4% in 2003 to 12.3% in 2017 in the same age group (90). In this same period in the Maule region, the prevalence was 11.1% to 10.2%.

Diabetes is a high -cost disease mainly due to its complications when it is not: renal failure, blindness, neuropathy and diabetic foot. In Chile, 10.2% of the health budget is used for diabetes care.

Insulin treatment is prevalent in diabetic people in Chile since the National Health System has only metformin, glibenclamide and insulin for the control of diabetes and supplies for blood glucose monitoring (SBGM). There are insufficient data on patients treated with insulin, and most reports suggest that they are insufficiently compensated.

Therefore, and objective of this line of research, is to fill this gap and evaluate the alternative management of these high -risk diabetic people, through a program with continuous glucose monitoring devices, which will be applied to the population of Mauco and patients will achieve a better and faster metabolic control than the standard of care in the ambulatory clinic.

Principal Researcher: Sandra Cortés

The beginning and the progression of chronic diseases (or noncommunicable diseases, ENT) are related to several well -studied risk factors, such as age, sex, diet, alcohol or tobacco consumption and a sedentary lifestyle.

Several environmental pollutants detected and that come into contact with humans through air, soil, water and food have been linked to the appearance of ENT. Pesticides, metals and other emerging pollutants are measured in industrial and agricultural areas, and in cities; These chemical compounds have been associated with reproductive, respiratory and nephrotoxic effects, as well as with cancer. In addition, current pesticides are endocrine disruptors because they imitate changes in hormonal function in thyroid, liver, kidneys and pancreas.

There are worldwide concerns that permanent exposure to low doses of pesticide mixtures, through occupation but also air and diet, has been associated with an increase in type 2 diabetes mellitus (DM2), a silent murderer globally in adults.

Hypothesis: exposure to pesticides is detectable and measurable in biological samples of Mauco participants, and their highest levels increase the levels of metabolic parameters related to the metabolism of glucose and lipids.

Principal researcher: Vinicius Maracaja

More than 90% of the mammalian genome is transcribed in coding and non -coding RNAs, which together compose the complex communication and regulation networks that finely adjust different cellular processes. Post-transcriptive events (that is, the junction, the modification of the RNA, the alternative polyadenilation) can modify the mode of action of an RNA, by changing the way in which it interacts with other RNA (RNA-ARN), proteins (RNA-Protein) or even with the DNA itself (formation of triplex RNA-ADN), drastically affecting the final biological processes For that transcript product.

It is known that different biological processes are associated with the different types of heart failure (IC), but the mechanisms influenced by different post-transcriptive events remain unclear. This new research line aims to integrate different experimental OMics data (generated internally and publicly available) and computational biology (that is, artificial intelligence, graph theory) to study the role of post-transcriptive events (that is, alternative splicing, Arn methylation, alternative polyadenilation) in IC.

Our interest feeds on the fact that regulatory networks can be directly affected by these events, influencing the RNAs interact with each other and with other molecules (RNA-ARN, RNA-Protein, RNA-ADN). We are eager to understand how post-transcriptive events generate a "disturbed network" both in the IC with preserved ejection fraction (ICFEP) and reduced (ICFER).