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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