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  1. ACC DiS Advanced Center forChronicDiseases

  2. Impact of the Scientific Problem: Chile’s Population PopulationStructure Mortalityby Cause 2010 1990 Cancer 24.6 Percentage Percentage Cardiovascular diseases 27.7 Females Males Females Males Prevalence of ChronicConditions NationalHeathSurvey - 2010

  3. Advanced Center forChronicDiseases General Aim: Toprovide a frameworkfortheunderstanding and prevention of thetwomainchronicdiseasesaffectingtheChileanpopulation. In associationwith a network of internationalcollaborators, ACCDiS aspires tobecoming a referencecenter in LatinAmericaforresearch and advanced training in chronicdiseases (CDs). • SpecificAims: • Todevelop a multidisciplinaryresearchinitiativethatwillpermitanalyzingthe natural history of cardiovascular diseasesand cancer in theChileanpopulation. • Toestablishspecificresearchlines in thearea of cancer and cardiovascular diseasescoveringbasic, clinical and epidemiologicalaspects and theirpublichealthconsequences. • To set up novel commonfacilitiesthatprovidestate of the art supportforthebasic, clinical and epidemiologicalresearch and training units. • Totrainadvanced human resources in CDs in collaborationwithourinternationalpartners. • Tocommunicatetothegeneral publicCD-relatedinformationand educate in diseaseprevention.

  4. Advanced Center forChronicDiseases BASIC CORE EPIDEMIOL CORE CLINICAL CORE Sergio Lavandero Director CardiovascDis CatterinaFerréccio Deputy Director Epidemiology-Cancer Andrew Quest PI Cancer Marcelo Kogan PI Nanomedicine Alejandro Corvalan PI Cancer Pablo Castro PI CardiovascDis = 20 + 14 Associated Investigators (AIs) Average age 48 yrs 12 Postdocs 38 PhDs 5 MSc 9 Undergraduate students 10 Professionals 13 Technicians = 87 40% 60% Previous collaborative interactions: Grants: AQ-SL (FONDAP CEMC, Ring), CF-AC (FONDEF grant), SL-PC (FONDECYTs), etc. Papers:High level productivity (last 5 years): 215 papers in peer-reviewed journals, 23 joint papers between two groups. 47 in 10% top journals, average impact factor: 4.5. 25% foreigners

  5. Facultad de Ciencias Químicas y Farmacéuticas • Sergio Lavandero. Depto de Bioquímica y Biología Molecular. • Marcelo Kogan. Depto de Química Farmacológica y Toxicológica. • Andrew Quest. Depto de Bioquímica y Biología Molecular. • Guillermo Díaz. Depto de Química Farmacológica y Toxicológica. • Lorena García. Depto de Bioquímica y Biología Molecular. • Soledad Bollo. Depto de Química Farmacológica y Toxicológica. • Carmen Romero. Depto de Bioquímica y Biología Molecular. • Felipe Oyarzún. Depto de Ciencias y Tecnología Farmacéuticas. • Mario Chiong. Depto de Bioquímica y Biología Molecular.

  6. Collaborative Research Maule Cohort (MAUCO)Rolando de la Cruz, Claudia Bambs, Pablo Toro and the six ACCDiS groups The epidemic of chronic diseases is associated with lifestyle and environmental changes and interactions with the genetic background of the population, which create unique disease profiles. The county of Molina (Maule region) with a high burden of chronic diseases is an ideal setting for population-based studies designed to identify key factors involved in disease development. Aims: To measure at baseline and follow-up on: • Risk factors: a) Socioeconomic and occupational; b) Psycho-social and lifestyle; c) Environmental; d) Chronic infections and inflammation; e) Genetic and ethnic. • Health biomarkers and disease-related events: a) Cardiovascular and metabolic outcomes; b) Cancer; c) Nutrition; d) Aging; e) Respiratory diseases. Chronic diseases share common risk factors and most of them are preventable Molina Methods: Population-based prospective cohort of 10,000 subjects aged >45 yrs, residents of Molina county. Collect biological samples and conduct an epidemiological survey (Biobank and Databank).

  7. Line 1: Metabolism and Cardiovascular SignalingSergio Lavandero (PI), Mario Chiong (AI), Zully Pedrozo (AI) Cardiovascular metabolismisinvolved in thegenesis and progression of cardiovascular diseases Aim 1 Mitochondrialdynamics in the control of cardiomyocyte/vascular smoothmusclecellmetabolism and remodeling. Aim 2 Mitochondrial-endoplasmicreticuluminteractionin the control of cardiomyocyte/VSMC metabolismand remodeling. Cell primary cultures WT & KO mice Aim 3 Signalingpathwayscontrollingmetabolism in cardiomyocyte/VSMC byAngiotensin-(1-9) and insulin. Aim 4 Prognosticvalue of IGF-1, insulin, GLP-1 and exosomes in theincidence of cardiovascular diseases in MAUCO. Ang-(1-9) Insulin IR AT2R ? Molina MAPKs Akt Ca2+ ?

  8. Line 2: Emerging Biomarkers in Heart Failure Pablo Castro (PI), Hugo Verdejo (AI), Ramón Corbalán (AI) Galectin-3 is a keybiomarker in heartfailure, promotingbothcardiacremodeling &mitochondrialdysfunction. Decrease in galectin-3 levelspreventsmyocardialremodeling Cardiomyocyte primary culture To evaluate the role of galectin-3 on mitochondrial morphology and metabolism in cultured cardiomyocytes Aim 1 Murinesevere TAC model The effect of pharmacological and genetic modulation of galectin-3 in a murine model of heart failure Aim 2 The correlation of galectin-3 and miRNAmarkers with myocardial dysfunction and fibrosis in high-risk heart failure (HF) patients Myocardialstrainimaging in HF patients Aim 3 Molina Emerging biomarkers in predicting adverse cardiovascular events in general population, using the Maule cohort (MAUCO) General population Aim 4

  9. Line 3: Inflammation in Angiogenesis, CellMigration, Metastasis Andrew Quest (PI), Lisette Leyton (AI), Carmen Romero (AI) • Pro-inflammatory stimuli (Prostaglandin E2, Helicobacter pylori) promote survivin dependent tumor angiogenesis and caveolin1-enhanced metastasis • Survivinexpression in tumor cells favors angiogenesis by promoting β-catenin/Tcf-Lef-dependent transcription of VEGF via a PI3K/Akt-mediated pathway • Pro-inflammatory stimuli disrupt E-cadherin/caveolin-1 surface complexes and promote β-catenin/Tcf-Lef- and HIF-1α-dependent transcription of survivin, cox2 and vegf • Pro-inflammatory stimuli activate NADPH oxidases and Src-family kinases, liberate caveolin-1 from E-cadherin/caveolin-1 surface complexes and promote migration/invasion via caveolin-1 enhanced tyrosine-14 phosphorylation and Rac1 activation Aim 1 Cell culture Chick CAM assay Aim 2 Murine tumor model Aim 3 Molina MAUCO In the cohort, look for microRNAs specific for caveolin-1 and E-cadherin (early phase) and caveolin-1 exosomes(metastasis marker)

  10. Line 4: Biomarkers for Early Detection of Gastric Tumors Alejandro Corvalan (PI), Gareth Owen (AI) To identify the early steps of gastric cancer through the detection of DNA methylation Reprimobiomarker on gastric carcinoma Aim 1 Role of coding/noncoding genes associated with vascularogenic mimicry and stemness in tumor dissemination at dysplasia Biomarkers Aim 2 Reprimo methylation is a plasma biomarker for early stages of gastric cancer development (dysplasia) Potential biomarkers of the process of tumor dissemination at dysplasia Aim 3 Vascularogenic mimicry and stemnessare key events at early stages of gastric cancer development (dysplasia) Tumor dissemination on isolated circulating tumor cells from dysplasia Aim 4 Diagnostic value of plasmatic levels of specific microRNA in the screening of gastric cancer in the Maule cohort Aim 5 Presence of a lumen

  11. Line 5: Natural History of Gallbladder Cancer (GBC)Catterina Ferreccio (PI), Juan Carlos Roa (AI), Sandra Cortés (AI) 20 GBC prevalence The risk of developing GBC is associated with inflammatory markers Gallbladder cancer is associated with an unique inflammatory profile, enterobacteria, genetic polymorphisms, Amerindian ancestry, chemical pollutants. - + Aim 1 10 The risk of developing GBC is associated with chronic infection by enterobacteria Aim 2 Santiago MAUCO Genetic polymorphisms and Amerindian markers are associated with metabolic inflammation and GBC 0 2000 2005 2010 Aim 3 Chemical pollutants in food –aflatoxins, pesticides- are risk factors of GBC. Aim 4 Methods: 1,000 people at higher risk gallbladder cancer from MAUCO. GB disease (10%), altered lipids (20%), diabetes (7%), obesity (30%) will be followed with abdominal Sonograph, samples of blood, urine and stool, identifying occurrence of disease.

  12. Line 6: Nanomedicine & NanotheranosticsMarcelo Kogan (PI), Soledad Bollo (AI), Ignacio Moreno (AI) Galectin-3 and REPRIMO by Biacore, AFM and BEAMing techniques Aim 1 Spatial and temporal release of antitumor drugs Aim 2 To track metastasis Nanotechnology in diagnostics and treatment of cancer and cardiovascular diseases Aim 3 Targeting the heart after myocardial infarction for theranostics Aim 4 To develop biosensors for highly sensitive determination of plasma biomarkers in MAUCO samples

  13. ACCDiSFacilities

  14. CoreFacility 1: MAUCO Biobank and Databank Molina

  15. CoreFacility 2: Inflammation and microRNAs

  16. CoreFacility 3: Functional& Experimental Animal Facility

  17. Advanced Human Capital Training To contribute actively to training and formation of young Chilean scientists, MDs and other health professionals in chronic diseases Seminars Workshops Summer courses Health professionals training PhD & MSc Thesis Co-direction Postdocs Co-direction Training opportunities in our international-national network Activities in 8 national PhD programs: Regular courses Establish the first PhD program in Epidemiology in Chile Undergraduate courses and training Some Associate Investigators will become PIs in the second period (2019-2024)

  18. Networking & CollaborationStrategy Establish national and international collaborations with individual groups, research centers & institutions. Actions: collaborative research, co-direction PhD theses-postdocs, joint papers, courses, conferences and symposia. NATIONAL UNIVERSITIES Universidad de Talca Pontificia Universidad Católica del Maule Universidad de Tarapacá Pontificia Universidad Católica de Chile Universidad de Chile USACH Universidad de Concepción Universidad de la Frontera Universidad Austral HOSPITAL & HEALTH INSTITUTIONS Hospitales Dipreca, San Juan de Dios, Salvador, Sótero del Río Ministerio de Salud Hospital Regional de Temuco OTHERS RESEARCH CENTERS FONDAP Center forGenomicRegulation MilleniumBiomedicalNeuroscienceInstitute National Center for Genomics, Proteomics and Bioinformatics -OMICs Nanotech INTERNATIONAL CELL BIOLOGY AREA Universidadede São Paulo Mount SinaiSchool of Medicine- New York NANOBIOMEDICINE AREA Instituteof Biomedical Research- Barcelona Instituteof Bioengineering of Catalonia Universidad Nacional de Córdoba EPIDEMIOLOGY AREA Johns Hopkins School of Medicine-Baltimore London School of Hygiene & Tropical Medicine Universityof Wisconsin-Madison Universityof California-Berkeley CANCER AREA NationalCancerInstitute, NIH Universityof Alberta TheUniversity of Western Australia VanderbiltUniversity-Nashville CARDIOVASCULAR AREA Universityof Texas Southwestern Medical Center- Dallas EmorySchool of Medicine-Atlanta The Hatter Cardiovascular Institute, UCL, London

  19. SCIENTIFIC COMMITTEE • JacqueCuzick.Universityof London, London, UK. • John Cidlowski. NationalInstitutes of EnvironmentalHealthSciences, NIH, USA • MariellL. Jessup. University of Pennsylvania HealthSystem and American HeartAssociations • Balz Frei. Linus Pauling CancerInstitute (LPI). OregonStateUniversity, Corvallis, Oregon, USA • Nelson Duran. Universidad de Campinas, Brazil

  20. ADVISORY COMMITTEE • Director ACCDiS • Director FONDAP • Director FONIS • Subsecretario de Salud‐ Ministerio de Salud • Director de Salud del Maule • Sociedad Chilena de Cardiología • Corporación Nacional del cáncer (CONAC) • Organización Panamericana de la Salud (OPS)

  21. INTERNATIONAL EVALUATION BOARD • HollyM. Brown-Borg.University of North Dakota, USA • James Galvin.New York University, USA • William Haley.TheUniversity of South Florida, USA • MikaelJansson.Centre forAddictionsResearch of British Columbia, Canada • AnneMarie Lompre.Universite Pierre et Marie Curie (UPMC), France • Jeff Sands.EmoryUniversity, USA

  22. Outreach We aspire to communicating to the non-specialized community information concerning cancer and cardiovascular diseases. Scientific Cell Biology Coffee: informal discussions about “hot topics” in cell biology over coffee • Program of outreach activities • Cycle of conferences for general audiences • Lectures at high schools • Summer Camps for secondary school students • Chronic disease video capsules (2) • Meetings with business men and politicians • Participation in Explora(CONICYT Outreach Program) • Web page - Social Networks • Hiring of communications and media training consultants

  23. SelectedIndicators Research • Technology transfer Formation of advanced human resources Collaboration Outreach