advanced center for chronic diseases 1. cancer 24.6 impact of the scientific problem: chile’s...
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DiSACCAdvanced Center for Chronic Diseases
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Cancer 24.6
Impact of the Scientific Problem: Chile’s Population
(%)High Blood Pressure 29.2Smoking 41.0Overweight 39.3Diabetes Mellitus 9.4Sedentarism 88.6High Cholesterol 38.5High CV Risk 17.7Salt intake > 5 g/day 99.0High risk alcohol consumption (EBBA) 17.7Cognitive impairment among >60 years 10.4
Population Structure1990 2010
Percentage
Males Females
Percentage
Males Females
Mortality by Cause
Prevalence of Chronic ConditionsNational Heath Survey - 2010
Cardiovascular diseases
27.7
Life expectancy 74.3 79.1
% population growth 1.6 0.9
Infant mortality rate 23.6 7.4
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Specific Aims: To develop a multidisciplinary research initiative that will permit analyzing the
natural history of cardiovascular diseases and cancer in the Chilean population. To establish specific research lines in the area of cancer and cardiovascular diseases
covering basic, clinical and epidemiological aspects and their public health consequences.
To set up novel common facilities that provide state of the art support for the basic, clinical and epidemiological research and training units.
To train advanced human resources in CDs in collaboration with our international partners.
To communicate to the general public CD-related information and educate in disease prevention.
General Aim: To provide a framework for the understanding and prevention of the two main chronic diseases affecting the Chilean population. In association with a network of international collaborators, ACCDiS aspires to becoming a reference center in Latin America for research and advanced training in chronic diseases (CDs).
Advanced Center for Chronic Diseases
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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.
BASIC CORE EPIDEMIOL CORE CLINICAL CORE
Sergio LavanderoDirector
Cardiovasc Dis
Andrew QuestPI
Cancer
Marcelo KoganPI
Nanomedicine
Catterina FerréccioDeputy Director
Epidemiology-Cancer
Alejandro CorvalanPI
Cancer
Pablo CastroPI
Cardiovasc Dis
= 8713 Technicians
10 Professionals
9Undergraduate
students
38 PhDs
5 MSc
12 Postdocs
+ 14 Associated Investigators (AIs) 40% 60%
Average age48 yrs
25% foreigners
= 20
Advanced Center for Chronic Diseases
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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.
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Molina
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.
Chronic diseases share common risk factors and most of them are preventable
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).
Aims: To measure at baseline and follow-up on: 1. Risk factors: a) Socioeconomic and
occupational; b) Psycho-social and lifestyle; c) Environmental; d) Chronic infections and inflammation; e) Genetic and ethnic.
2. Health biomarkers and disease-related events: a) Cardiovascular and metabolic outcomes; b) Cancer; c) Nutrition; d) Aging; e) Respiratory diseases.
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Line 1: Metabolism and Cardiovascular Signaling Sergio Lavandero (PI), Mario Chiong (AI), Zully Pedrozo (AI)
Mitochondrial dynamics in the control of cardiomyocyte/vascular smooth muscle cell metabolism and remodeling.
Mitochondrial-endoplasmic reticulum interaction in the control of cardiomyocyte/VSMC metabolism and remodeling.
Signaling pathways controlling metabolism in cardiomyocyte/VSMC by Angiotensin-(1-9) and insulin.
Prognostic value of IGF-1, insulin, GLP-1 and exosomes in the incidence of cardiovascular diseases in MAUCO.
Cardiovascular metabolism is involved in the genesis and progression of cardiovascular diseases
AT2R IR
MAPKs Akt Ca2+
?
?
Ang-(1-9) Insulin
Molina
Aim 1 Aim 2
Aim 3 Aim 4
Cell primary cultures
WT & KO mice
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Line 2: Emerging Biomarkers in Heart Failure Pablo Castro (PI), Hugo Verdejo (AI), Ramón Corbalán (AI)
Cardiomyocyte primary culture
Aim 1
Aim 2
Aim 3
Aim 4
To evaluate the role of galectin-3 on mitochondrial morphology and metabolism in cultured cardiomyocytes
The effect of pharmacological and genetic modulation of galectin-3 in a murine model of heart failure
Murine severeTAC model
The correlation of galectin-3 and miRNA markers with myocardial dysfunction and fibrosis in high-risk heart failure (HF) patients
Myocardial strain imaging in HF
patients
Emerging biomarkers in predicting adverse cardiovascular events in general population, using the Maule cohort (MAUCO)
General population
Galectin-3 is a key biomarker in heart failure, promoting both cardiac remodeling & mitochondrial dysfunction. Decrease in galectin-3 levels prevents myocardial remodeling
Molina
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Survivin expression 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
Line 3: Inflammation in Angiogenesis, Cell Migration, MetastasisAndrew Quest (PI), Lisette Leyton (AI), Carmen Romero (AI)
Pro-inflammatory stimuli (Prostaglandin E2, Helicobacter pylori) promote survivin dependent tumor angiogenesis and caveolin1-enhanced metastasis
Survivin
Tcf/Lef
b-catenin
b-catenin
Nucleus
Cytoplasm
VEGF
AktPI3K
AngiogenesisVEGF
Aim 3
Cytoplasm
PGE2
H. pyloriCaveolin-1
E-cadherin
b-catenin
Src
Y14 PI3K
Rab-5
Rac-1
GTPGDP
Adaptor
Tiam-1
GTPGDP
Migration
H. pylori b-catenin
Tcf/Lef
b-catenin
Nucleus
Cytoplasm
Survivin
Cox-2
VEGF
b-catenin
HRE
Hif-1
Hif-1
Aim 2
Caveolin-1
PGE2
E-cadherin
Aim 1
Aim 2
Aim 3
Cell culture
Murine tumor model
MAUCO
MolinaIn the cohort, look for microRNAs specific for caveolin-1 and E-cadherin (early phase) and caveolin-1 exosomes (metastasis marker)
Chick CAM assay
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Reprimo methylation is a plasma biomarker for early stages of gastric cancer development (dysplasia)
Aim 1
Aim 2
Aim 3Vascularogenic mimicry and stemness are key events at early stages of gastric cancer development (dysplasia)
Line 4: Biomarkers for Early Detection of Gastric TumorsAlejandro Corvalan (PI), Gareth Owen (AI)
Aim 4
Aim 5
Biomarkers
To identify the early steps of gastric cancer through the detection of DNA methylation Reprimo biomarker on gastric carcinoma
Role of coding/noncoding genes associated with vascularogenic mimicry and stemness in tumor dissemination at dysplasia
Potential biomarkers of the process of tumor dissemination at dysplasia
Tumor dissemination on isolated circulating tumor cells from dysplasia
Diagnostic value of plasmatic levels of specific microRNA in the screening of gastric cancer in the Maule cohort
Presence of a lumen
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Line 5: Natural History of Gallbladder Cancer (GBC)Catterina Ferreccio (PI), Juan Carlos Roa (AI), Sandra Cortés (AI)
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.
Gallbladder cancer is associated with an unique inflammatory
profile, enterobacteria, genetic polymorphisms, Amerindian ancestry, chemical pollutants.
The risk of developing GBC is associated with inflammatory markers
Aim 1
Aim 2
Aim 3
Aim 4
The risk of developing GBC is associated with chronic infection by enterobacteria
Genetic polymorphisms and Amerindian markers are associated with metabolic inflammation and GBC
Chemical pollutants in food –aflatoxins, pesticides- are risk factors of GBC.
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10
02000 2005 2010
MAUCO
Santiago
GBC prevalence
- +
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Line 6: Nanomedicine & NanotheranosticsMarcelo Kogan (PI), Soledad Bollo (AI), Ignacio Moreno (AI)
Department of Bioengineering, College of Engineering, Hanyang University, IT BT building.
Nanoparticles for therapy and diagnostic (Theranosis)
To track metastasisSpatial and temporal release of antitumor drugs
Targeting
Pharmacologic activity
Targeting
Pharmacologic activity
Tumor cellTumor cell
Cell internalizationlaser
Targeting
Pharmacologic activity
Targeting
Pharmacologic activity
Tumor cellTumor cell
Cell internalizationlaser
Targeting the heart after myocardial infarction for theranostics
Galectin-3Detection in blood
Magnetic nanoparticlesBEAMING
oligo
Galectin-3 and REPRIMO by Biacore, AFM and BEAMing techniques
Biodistribution in vivo (Fx-Pro) and ex vivostudies
Labelled tumor cells
injection
Biodistribution in vivo (Fx-Pro) and ex vivostudies
Labelled tumor cells
injection
Detection and treatment
laser
Detection and treatment
laser
Nanotechnology in diagnostics and treatment of cancer and
cardiovascular diseases
To develop biosensors for highly sensitive determination of plasma biomarkers in MAUCO samples
Aim 1 Aim 2
Aim 3 Aim 4
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ACCDiS Facilities
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Core Facility 1: MAUCO Biobank and Databank
Molina
Core Facility 2: Inflammation and microRNAs
Core Facility 3: Functional & Experimental Animal Facility
Advanced Human Capital Training
Establish the first PhD program in Epidemiology in
Chile
Activities in 8 national PhD
programs:Regular courses
PhD & MSc Thesis Co-direction
Health professionals
training
SeminarsWorkshops
Summer courses
PostdocsCo-direction
Training opportunities in our international-national network
Some Associate Investigators will become PIs in the second
period (2019-2024)
To contribute actively to training and formation of young Chilean scientists, MDs and other health professionals in chronic diseases
Undergraduatecourses and
training
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Networking & Collaboration Strategy
CANCER AREA1. National Cancer Institute, NIH2. University of Alberta 3. The University of Western
Australia4. Vanderbilt University-Nashville
CARDIOVASCULAR AREA5. University of Texas
Southwestern Medical Center- Dallas
6. Emory School of Medicine-Atlanta
7. The Hatter Cardiovascular Institute, UCL, London
NANOBIOMEDICINE AREA8. Institute of Biomedical
Research- Barcelona9. Institute of Bioengineering of
Catalonia 10. Universidad Nacional de
Córdoba
EPIDEMIOLOGY AREA11. Johns Hopkins School of
Medicine-Baltimore12. London School of Hygiene &
Tropical Medicine13. University of Wisconsin-
Madison 14. University of California-Berkeley
CELL BIOLOGY AREA15. Universidade de São
Paulo16. Mount Sinai School of Medicine- New York
NATIONALUNIVERSITIESUniversidad de TalcaPontificia Universidad Católica del MauleUniversidad de TarapacáPontificia Universidad Católica de ChileUniversidad de ChileUSACHUniversidad de ConcepciónUniversidad de la FronteraUniversidad Austral
HOSPITAL & HEALTH INSTITUTIONSHospitales Dipreca, San Juan de Dios, Salvador, Sótero del RíoMinisterio de SaludHospital Regional de Temuco
OTHERS RESEARCH CENTERSFONDAP Center for Genomic
RegulationMillenium Biomedical Neuroscience
InstituteNational Center for Genomics,
Proteomics and Bioinformatics -OMICs
Nanotech
INTERNATIONAL
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.
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SCIENTIFIC COMMITTEE
• Jacque Cuzick. University of London, London, UK.
• John Cidlowski. National Institutes of Environmental Health Sciences, NIH, USA
• Mariell L. Jessup. University of Pennsylvania Health System and American Heart Associations
• Balz Frei. Linus Pauling Cancer Institute (LPI). Oregon State University, Corvallis, Oregon, USA
• Nelson Duran. Universidad de Campinas, Brazil
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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)
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INTERNATIONAL EVALUATION BOARD
• Holly M. Brown-Borg. University of North Dakota, USA
• James Galvin. New York University, USA• William Haley. The University of South
Florida, USA• Mikael Jansson. Centre for Addictions
Research of British Columbia, Canada• Anne Marie Lompre. Universite Pierre et
Marie Curie (UPMC), France• Jeff Sands. Emory University, USA
Scientific Cell Biology Coffee: informal discussions about “hot topics” in cell biology over coffee
Outreach
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)
We aspire to communicating to the non-specialized community information concerning cancer and cardiovascular diseases.
Web page - Social Networks Hiring of communications and media training
consultants
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Selected IndicatorsIndicator Baseline
Average last 5 years
3 years 5 years
Cumulative Number of ISI Publications 43 135 230
Cumulative number of ISI publications at the top 10% of impact for the Center’s primary disciplines
4 14 25
Average impact of publications 4.5 4.8 5.0
Patent application 1 1 2
New Hires 0 2 4
Postdoctoral Fellows 2 10 19
Finished PhD Thesis 10 33 57
Indexed publications among members of every line of research 5 24 50
Number of post-graduate theses tutored among the members of each line of research
<1 9 15
Joint publications with international institutions or research centers 10 40 70
Joint projects with international institutions or research centers 2 8 14
Visiting researchers 3 12 20
International Workshops or Meetings in Chile, organized by the Center
2 7 12
Outreach articles 1 7 15
Outreach events (conferences, seminars, workshops, exhibitions) 3 14 25
Research
Collaboration
Formation of advanced human resources
Outreach
Technology transfer
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