Research Lines
Principal investigator: Sergio Lavandero
Associated researchers: Valentina Parra, Vinicius Maracajá, Zully Pedrozo, Mario Chiong, Alfredo Criollo
National partners: Lorena Garcia, Guillermo Díaz-Araya, Rodrigo Troncoso, Mariana Cifuentes, Roberto Bravo-Sagua, Jaime Riquelme
International collaborators: JA Hill & TG Gillette (UT Southwestern Medical Center, USA), S Davison & D Yellon (Hatter Cardiovascular Institute, UCL, London, UK), H Li (Wuham University, China), San Martín (Emory University, USA), D Westenbrink (University of Groningen, The Netherlands).
Heart failure is a clinical syndrome caused by a structural or functional disturbance of the heart that can result in a normal or reduced cardiac output at rest or during stress. It represents the final phase of various pathologies, cardiovascular or metabolic, include hypertension, myocardial infarction, arrhythmias, Diabetes, etc. Both incidence and prevalence has increased in the elderly due to the increase in the life expectancy in recent decades. Heart failure is considered “the epidemic of the 21st century” and a major challenge for public health, especially in countries with increasingly aged populations.
The cardiac work requires significant amounts of energy generation (ATP), which is provided by the mitochondrial metabolism. In the hearts with failure there is depletion of energy, what you have raised how hypothesis that alterations in the morphology and mitochondrial function and its interaction with other organelles are involved in the genesis and progression of heart failure already is with reduced ejection fraction (HFrEF) or preserved (HFpEF).
Our goals are:
- Evaluate the role of morphology and Mitochondrial Metabolism and communication mitocondria-reticulo reticulum in cardiomyocytes and vascular smooth muscle cells in the genesis and progression of the HFpEF and the HFrEF.
- How to assess inflammation regulates morphology and Mitochondrial Metabolism in the genesis and progression of HFpEF and HFrEF.
- Investigate the signaling pathways that control metabolism and inflammation by cytokines, VCAM1, galectina-3, Angiotensin-(1-9), insulin and IGF-1 in HFpEF and HFrEF.
- Assess the Association of cardiovascular health index, echocardiographic markers and inflammatory with the incidence of HFpEF and HFrEF in the cohort of Maule.
Principal investigator: Pablo Castro
Associated researchers: Luigi Gabrielli, María Paz Ocaranza, Hugo Verdejo
National partners: Ramón Corbalán, Clara Quiroga
International collaborators: JA Hill & TG Gillette (UT Southwestern Medical Center, USA), D Westenbrink (University of Groningen, The Netherlands), Marta Sitges (Hospital Clínic, Barcelona, Spain).
Heart failure, the common final stage of several cardiovascular diseases, It is a global pandemic which affects 26 million people around the world, the majority of which are women. From a physiological point of view, heart failure is defined as the inability of the heart to support the cardiac output required to meet the metabolic demands of the body, In addition to increasing left ventricular filling pressure. A standard way to classify heart failure is according to the degree of deterioration of the ejection fraction of the left ventricle which defines three subtypes, namely, heart failure with reduced ejection fraction (HFrEF), with preserved ejection fraction heart rate (HFpEF) and midrange ejection fraction (HFmrEF). The majority of clinical trials have focused on HFrEF, a subtype of most common failure in men against which the majority of pharmacological therapies are directed. In reverse, the HFpEF, the form most prevalent in women, It is not well known and are missing specific pharmacological therapies. Our hypothesis is that the clinical differences between male and female cardiac insificiencia patients depend on differences related to gender in the cardiac structure, miRNA signage, metabolism and immunity.
Our specific objectives are:
- Evaluate the differences related to gender in the inflammation and remodeling of the heart in patients with heart failure.
- Determine the expression of Mirna biased by sex in patients with heart failure and its relationship with the remodeling of the heart, inflammation and metabolism.
- To assess changes related to gender in inflammation and early remodeling of the myocardium in the general population of MAUCO cohort.
- Assess the impact of the modulation of estrogen in a mouse model of HFpEF.
Principal investigator: Andrew Quest
Associated researchers: Lissette Leyton, Vicente Torres, Lorena Lobos
National partners: Carmen Romero, Denise Bravo, Marcela Hermoso, Manuel Valenzuela
International collaborators: V Perez (Linus Pauling Institute, USA), C Solomon (University Queensland, Australia), C Rovira (University Lund, Sweden), Pascal Schneider (University Lausanne, Switzerland), Wael Rifa'i (University Miami, USA), Chris Abneter (NCI, USA).
Gastric cancer is the leading cause of deaths related to cancer in Chile and infection by Helicobacter pylori (HP), is highly prevalent in the country (around 70-80% of the population), is considered a risk factor important for development. disease. Given our previous work with Hp, focused on gamma glutamyl transpeptidase (GGT) and urease, and our broad interest in signalling activated by extracellular vesicles (EV) of different origin, We will focus here on the study of cell death induced by H. pylori and proinflammatory signaling triggered by GGT soluble virulence factors and urease, as well as by the bacterial outer membrane vesicles (OMV).
Our specific objectives are:
- Determine how the Hp gamma glutamyl transpeptidase alters the protein kinase R (PKR) like ER kinase (PERK) to promote the loss of survivina and gastric cell death.
- Determine if the virulence factor of the urease of Helicobacter pylori induces 1a factor induced by hypoxia via activation of TLR2/4 type receptors
- Determine if the loss of E-cadherin in patient samples is attributable to Rab5-dependent Endocytosis and / or to the silencing of E-cadherin-dependent DNA-methyl transferases.
- Demonstrate that joint incubation of Helicobacter pylori with Porphyromonus gingivalis increases the virulence of Helicobacter pylori.
Principal investigator: Alejandro Corvalan
Associated researchers: Gareth Owen, Francisco Aguayo
National partners: Enrique Norero, Gonzalo Carrasco-Avino, Marcelo Andia, Patricio González and Mauricio Cuello.
International collaborators: 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 declined in recent decades, It continues to be a global public health problem. Gastric cancer is the fifth most common cancer and the third leading cause of death associated with cancer throughout the world. In addition, gastric cancer has marked geographic variations with high mortality rates in the countries of Asia and Latin America and the lowest in the U.S.. UU., Canada and Australia. These geographical variations could be related to the role of the genetic descent or ancestry ethnic incidence and prognosis of gastric cancer. In addition, Coevolution pathogens associated with gastric cancer (H. pylori and Epstein-Barr virus, EBV) It could also contribute to these geographical variations. In this complex and heterogeneous scenario, our proposal will expand our previous epigenomic approach (methylation of DNA and microRNAs) new and emerging aspects of gastric cancer.
Our specific objectives are:
- Identify genetic variations in germ line genes of microRNA targeting CDH1 found negative for mutations in CDH1
- Identify the deregulation epigenomic the synergistic effect between the oncoproteins of EBV and environmental factors in gastric cancer associated with EBV-associated (EBVaGC).
- Investigate the role of exosomes and miRNA in the metastaisca of gastric cancer spread.
- Predict response to treatment based on biomarkers of free cells methylated DNA (cfDNA).
Dr's Laboratory. Alejandro Corvalan
Dr's Laboratory. Francisco Aguayo
Principal investigator: Catterina Ferreccio
Associated researchers: Juan Carlos Araya, Sandra Cortés
National partners: Ricardo Verdugo, Marco Arrese, Claudio Vargas, Rafael araos, Claudia Foerster
International collaborators: J Koshiol & To 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 more gallbladder cancer mortality worldwide; Until 2010, gallbladder cancer was the first killer of cancer 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 gallstones is the abnormal lipid metabolism associated with obesity and female hormones. Chileans have one of the highest prevalence rates of gallstones reported, with a surprising sex differential. In MAUCO, at the age of 35 to 44 years, the women had one prevalence of 5 times greater than the gallbladder disease than men (36% compared with 7%), the sex ratio was reduced to only 1,6 at the age of 65 years (62 vs. 38% ).
Our specific objectives are:
- Identify the role of sex, Amerindian ancestry and genetic factors known in the occurrence of gallstones and their progression to precancerous lesions. Explore the interaction of genetic susceptibility with diet, the chemicals (pesticides, mycotoxins), blood lipids and sex hormones. Study GBD family groups.
- Investigate the elements of the causal chain from obesity to Dyslipidemia, systemic inflammation, chronic cholecystitis and precancerous lesions.
- Study the microbial profile of persons with normal gallbladder, cholecystectomy and gallstones. Explore the Association of the profile of the microbiomas with the chronic transport of H. pylori and S. typhi, diet and ancestry.
- Determine if the removal of the gallbladder modified lipid profile and the fat content of the liver. To explore whether these effects are associated with changes in the Microbiome.
- Identify the genetic and environmental factors common to the GBD, diabetes, cardiovasculas disease and stroke.
Principal investigator: Marcelo Kogan
Associated researchers: Soledad Bollo, Andronikos Neira, Felipe Oyarzun, Javier Morales
National partners: Eyleen Araya, Natalia Hassan
International collaborators: E Giralt (Institute of Biomedical Research Barcelona, Spain), F Albericio (University of Barcelona, Spain), J Samitier (Institute of Bioengineering of Catalonia, IBEC, Barcelona), GA Rivas, (University of Cordova, Argentina), LJ Cruz (University of Leiden, The Netherlands).
This line of research of nanomedicine has collaborative projects with different lines of research of ACCDiS. For continuity plan, We focus our research in nanomedicine and chemical and pharmaceutical sciences the following topics: Improvement of administration and stability of medicaments for the treatment of cardiovascular diseases and cancer. The formulation of drugs is important for the development of successful therapies. In this context, selective management is important to reduce the side effects and the premature release of the drug in a drug from the formulation should be avoided. In this sense, the therapeutic effectiveness should be improved achieving controlled spatial and temporal release of therapeutic payload via the use of systems of administration of drugs that respond to external stimuli. On the other hand, formulations can improve the pharmaceutical properties of a drug, as the average life and the solubility. With this in mind, We propose the following hypothesis: “The use of nanovehicles improves the delivery of anti-tumor drugs and angiotensin-(1-9)”.
Our specific objectives are:
- Improve the management of anti-tumor drugs and angiotensin-(1-9).
- Using exosomes to target organs and tumors specific drugs.
- Combine nanostructures with molecules targeting the heart tissue to a selective supply of drugs.
- Detect biomarkers ultra-sensitive and specifically linked to cancer or cardiovascular diseases.
Principal Investigator: Mariana Cifuentes
Chronic diseases associated with obesity such as type 2 diabetes, Cardiovascular diseases and certain types of cancer are one of the leading causes of morbidity and death in the world, and three out of four Chileans over the age of 15 are overweight or obese. These diseases are the result of fat tissue in obesity becoming dysfunctional, associated with a pro-inflammatory state.
However, Not everyone with obesity develops metabolic complications, which has led to the concept of “Metabolically Healthy Obesity” (MHO, For its acronym in English). Although the clinical differences between MHO and obesity are metabolically not healthy (MUO) have been widely described, The cellular and molecular mechanisms involved in the establishment of these phenotypes are largely unknown.
Our goal is to understand the mechanisms within adipose tissue and in its communication with other cells and organs, that make a person with obesity may or may not have the aforementioned alterations. In particular, we are interested in inflammatory mechanisms, that are transversal to a large number of chronic diseases, as well as the mechanisms of communication between cells and organs mediated by extracellular vesicles.
Principal Investigator: Laura Andrea Huidobro
Type 2 Diabetes Mellitus (DM2) It is a highly prevalent disease around the world. According to the National Health Surveys, in Chile, 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 ranged from 11.1% to 10.2%.
Diabetes is a high-cost disease mainly due to its complications when left untreated: Renal impairment, blindness, Neuropathy and Diabetic Foot. In Chile, 10.2% of the health budget is allocated to diabetes care.
Insulin treatment is prevalent in diabetic people in Chile since the National Health System only has Metformin, Glibenclamide and Insulin for Diabetes Management and Blood Glucose Monitoring Supplies (SBGM). There are insufficient data on patients treated with insulin, and most reports suggest that they are undercompensated.
Therefore, Objective of this line of research, is to fill this gap and evaluate alternative management of these high-risk diabetics, through a program with continuous glucose monitoring devices, which will be applied to the MAUCO population and patients will achieve better and faster metabolic control than the standard of care in the outpatient clinic.
Principal Investigator: Sandra Cortés
The Onset and Progression of Chronic Diseases (or non-communicable diseases, ENT) are linked to several well-studied risk factors, such as age, Sex, Diet, alcohol or tobacco use and a sedentary lifestyle.
Various environmental pollutants detected and coming into contact with humans through the air, The Soil, water and food have been linked to the onset of NCDs. Pesticides, Metals and Other Emerging Pollutants Measured in Industrial and Agricultural Areas, and in cities; These chemical compounds have been associated with reproductive effects, respiratory and nephrotoxic, as well as with cancer. In addition, Today's pesticides are endocrine disruptors because they mimic changes in hormonal function in the thyroid, The liver, the kidneys and pancreas.
There are concerns globally 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 killer on a global level in adults.
Hypothesis: Pesticide exposure is detectable and measurable in biological samples from MAUCO participants, and their higher levels increase the levels of metabolic parameters related to glucose and lipid metabolism.
Principal Investigator: Vinicius Maracajá
More than 90% of the mammalian genome is transcribed into coding and non-coding RNAs, that together make up the complex communication and regulatory networks that fine-tune different cellular processes. Post-transcriptional events (i.e., Splicing, RNA modification, Alternative polyadenylation) can modify the mode of action of an RNA, by changing the way it interacts with other RNAs (RNA-RNA), proteins (RNA-protein) or even with the DNA itself (RNA-DNA triplex formation), drastically affecting the final functional biological processes regulated by that transcribed product.
Different biological processes are known to be associated with different types of heart failure (IC), But the mechanisms influenced by different post-transcriptional events remain unclear. This new line of research aims to integrate different experimental omics data (Generated internally and publicly available) and Computational Biology (i.e., artificial intelligence, Graph Theory) to study the role of post-transcriptional events (i.e., Alternative Splicing, RNA methylation, Alternative polyadenylation) in the CI.
Our interest is fueled by the fact that regulatory networks can be directly affected by these events, influencing the way RNAs interact with each other and with other molecules (RNA-RNA, RNA-Protein, RNA-DNA). We are eager to understand how post-transcriptional events generate a “Disrupted network” both in HF with preserved ejection fraction (ICFEp) as reduced (ICFEr).