Report

Fondation privée

reconnue d’utilité

publique

www.pasteur-lille.fr

2016

managed by Prof. Philippe Amouyel(PU-PH, Université De Lille) UMR1167 Inserm, Institut Pasteur de Lille,CHRU de Lille, Faculté de Médecine,Université de Lille

advancEs

CARDIOVASCULAR DISEASES:IDENTIFYING RISK FACTORSIN ORDER TO IMPROVEPREVENTION AND TREATMENT

Prof. Philippe amouyel's teamdevelops epidemiological re-search programs with the aimof understanding the role ofcardiovascular risk factors (genetics, excess body weight,obesity, type 2 diabetes, hyper-tension, cholesterol, smoking,etc.) in the onset and evolutionof myocardial infarction andstroke. their work is based onlille's morbidity register of ische-mic heart disease and stroke,which continuously inventoriesall cases of these diseases occurring within the metropoli-tan community of lille. medicalresearchers conduct their inves-tigations in public hospitals,emergency services and pri-vate hospitals endowed with

a cardiology or neurology department. the purpose ofthese studies is: • to understand the evolution

of vascular pathology interms of classification, mana-gement and prevention;

• to analyze the role of geneticand environmental deter-minants of cardiovascular diseases.

the institut pasteur de lille hasparticipated in and continuesto participate in internationalstudies such as monica (mo-nitoring of trends and deter-minants of cardiovosclar di-seases), prime (prospective oninfarction of the myocardium)or euroaSpire (european action on Secondary and pri-mary prevention by interventionto reduce events). what'smore, the research team in the Hauts-de-France region isconducting the eliSabet study"enquête littoral Souffle air

biologie environnement" – thecoastal breeze air biology envi-ronment study) which looks atthe impact of pollution on pulmonary and cardiovascularfunctions, as well as the geccoS study (gene-environ-ment in a case-control studyon obeSity), which studies thegenetic and environmental determinants associated withour dietary behavior and its impact on weight gain. a biolo-gical resource center ensuresthe logistics and storage of bio-logical samples and tissues thathave been gathered in thesevarious studies. For over thirtyyears, researchers have beenmonitoring the evolution of vascular risk factors, making the"Risk factors and molecular determinants of aging-relateddiseases" team a unique ob-servatory of these diseases inFrance!

16 / institut pasteur de lille / Research Report 2016

this unit focuses on the battle against cardiovascular and neurodegenerativediseases with a particular emphasis on cardiac arrests, strokes and alzheimer'sdisease. three teams interact within this unit. the first team is dedicated to"epidemiology and public health with respect to cardiovascular and cerebrovasculardiseases". the second, led by dr. Florence pinet (inserm research director), studiesthe "molecular determinants of heart failure and ventricular remodeling". the thirdteam, led by dr. jean-charles lambert (inserm research director), is working on the"molecular determinants of alzheimer's disease and cognitive impairment".

risk factors and moleculardeterminants of diseases linked to aging

Advances

Research Report 2016 / institut pasteur de lille / 17

DETECT AND PREVENT HEARTFAILURE IN ORDER TO FIGHTTHE AGING OF THE HEART

after a heart attack, the leftventricle can sometimes deformand the patient is found to havecardiac insufficiency: the heart isno longer able to pump enoughblood to meet the body'soxygen needs. people whosuffer from cardiac insufficiencyget out of breath and tire moreeasily. the survival rate five yearsafter the diagnosis is appro-ximately 50%. cardiac insuf-ficiency concerns 10% of peopleover 70. when the first signs ofthis cardiac insufficiency appearon the ultrasound exam, oneyear after the myocardialinfarction, the condition isalready irreversible. So when inthe early 2000s dr. Florence Pinetproposed to the lille universityHospital cardiologists working inthe unit to study these patients inorder to find earlier markers ofthis insufficiency, there were allfor it. an inserm research director,Florence pinet is a specialist inproteomics, a science that iscomplementary to genomics,which focusses on the study ofproteins, their functions andinteractions within cells. togetherwith Prof. christophe Bauters ofthe university Hospital of lille, shedesigned a clinical researchprotocol focused on hospitalizedpatients which led to the disco-very, in 2010, of a first biologicalmarker for left ventricular remo-deling following a first myo-cardial infarction. Since then,researchers have been develo-ping a dosage that can be used

in clinical routines. they continueto look for new markers in orderto be able to offer the mostcomplete test possible tomeasure the risk of developingcardiac insufficiency by meansof a simple blood sample. thisdiscovery, patented by insermand the institut pasteur de lille, is of interest to the diagnosticssector and should help toimprove treatments for heartattack victims by selecting thosethat can benefit, at the righttime, from circulatory assistanceor a heart transplant at theappropriate time.

WE ARE NOT ALL EQUAL IN THEFACE OF ALZHEIMER'S DISEASE:THE GENETIC TRAIL

alzheimer's disease is a neuro-degenerative condition of the

brain that causes progressivedisappearance of neurons. twomain lesions progressively invadethe brain and cause the death ofthe nerve cells:

• neuritic plaques or "senileplaques" this is a deposit, locatedoutside the neurones, mainlycomposed of the beta-amyloidprotein,

• neurofibrillary degeneration,that is, an aggregate of anotherprotein, the tau protein, in theform of abnormal filamentsactually found inside theneurones. the lesions remainsilent for a long time and thencause clinically detectable signsas they spread and impact areasthat are important to brainfunctioning. So that when clinicalsigns appear, the disease hasalready caused irreparabledamage within the brain, quiteoften for over ten years. Forresearch to progress, we need to find markers that will allow usto identify the disease as early as possible, before the first signsand while the extent of thelesions and the neuronal loss arestill limited. current research isfocused on four types of markers:cerebral markers that can be detected by means of a

Dr. Florence Pinet's team has shown that circulating plasma levels ofMMP-8 are a new predictor of ventricular remodeling (PatentEP12305722.6). In addition, this team was the first to show that thecirculating plasma levels of an lncRNA, LIPCAR, can predict survivalin patients with cardiac insufficiency (Patent EP14160577).

HIGHLIGHT

18 / institut pasteur de lille / Research Report 2016

Advances

spinal tap, morphological andfunctional markers detectedthrough cerebral imaging,blood markers that aredetected via a simple bloodsample, and genetic markersfrom an analysis of dna. thiswork is being developed inconjunction with a laboratoryof excellence known as disTalZ(development of innovativeStrategies for a transdiscipli-nary approach to alzheimer'sdisease). within this context,Jean-charles lambert's teamat the institut pasteur de lillehas been working on individualsusceptibility to alzheimer'sdisease and has thus been ableto identify most of the genesinvolved in the emergence ofthis illness. this research mustallow us to understand whycertain genes develop thedisease more frequently thanothers in order to offer treat-ments blocking the triggeringfactors and/or strengtheningthe protective factors.

HIGHLIGHT

In order to characterize thegenetic susceptibility toAlzheimer's disease, we havedeveloped a new Europeanproject called EADB (Euro-pean Alzheimer's DiseaseDNA Biobank) which willallow us to perform whole-genome genetic analyses onclose to 40,000 patients and65,000 controls. We havealso entered the field of veryhigh volume sequencing and are in the process ofanalyzing our first completegenome data from 1000patients and controls.

In GECCOS, (the Gene and Environment Case Control ObesityStudy) developed in collaboration with the Nutrition Department ofthe CHRU of Lille (headed by Prof. Romon) and the HealthPrevention Center of the Institut Pasteur de Lille, we haveinvestigated the influence of several dietary behaviors and attitudeson the risk of obesity. This study showed that of the 10 potential behaviors tested, eatingfrom a large plate, eating at night, and having an undisciplined dietare mediators of the relation that exists between socioeconomicstatus and obesity (the lower the socio-economic level, the higherthe risk of obesity) (Pigeyre M, Rousseaux J, Trouiller P, et al.) Int JObes. 2016).

HIGHLIGHT

Advances

Research Report 2016 / institut pasteur de lille / 19

Alzheimer's disease is the mostcommon of neurodegenerativediseases. Its prevalence doublesevery five years after age 65. Itleads gradually and inevitablyto cerebral neuronal death, inthe absence of a therapeuticsolution. In France, seven Frenchresearch units at the highestinternational level in the field ofAlzheimer's disease researchhave decided to unite their skillsto create a unique and multi-disciplinary laboratory of excel-lence: DISTALZ (Development ofInnovative Strategies for aTransdisciplinary Approach toALZheimer's disease). Five ofthese laboratories are located inLille, one in Nice and one inParis:

n Prof. Philippe AMOUYELUMR1167 «Risk factors andmolecular determinants of disea-ses linked to aging» (InstitutPasteur de Lille - Université Lille 2 - Faculty of Medicine -Inserm - CHRU de Lille)

n Prof. Frédéric CHECLERIPMC UMR7275 - Institute of Molecular and CellularPharmacology (CNRS - Inserm -Université Nice Sophia Antipolis,Nice-Valbonne)

n Dr. Luc BUEEUMR 1172, Jean-Pierre AubertResearch Center, Alzheimer'sand Tauopathies Team (Inserm -CHRU de Lille - Université Lille 2,Lille)

n Dr. Isabelle LandrieuUGSF - UMR8576 Structural andFunctional Glycobiology Unit(CNRS – Université de Lille 1,Villeneuve-d’Ascq)

n Prof. Florence PASQUIERResource and Research MemoryCenter (CHRU - Université Lille 2 -Faculté de Médecine, Lille)

n Prof. Pascal ANTOINEUMR 9193, Cognitive andAffective Sciences Research Unit(Université Lille 3, Villeneuve-d'Ascq)

n Prof. Emmanuel HIRSCHEA1610 «Ethical Space» (Uni-versité Paris Sud XI – APHP,Paris)

These units cover all the fieldsinvolved in the pathology: Thefundamental research, of course,with its particularly genetic,

biological and epidemiologicalaspects, the therapeutic approa-ches envisaged, but also theclinical field and the humansciences, not to mention theethical stakes involved. It is anoriginal transdisciplinary approachfacilitating work on the mostadvanced research hypotheses,taking into account the dailylives of patients and caregivers.

Coordinated by ProfessorPhilippe AMOUYEL (Universitéde Lille 2 - Faculty of Medicine,CHRU and Institut Pasteur deLille), DISTALZ epitomizes theexcellence of research suppor-ted by the Hauts-de-Franceregion on this disease in closecollaboration with Paris andNice, and positions itself as acenter of excellence in theinternational research commu-nity devoted to eradicatingAlzheimer's disease.

PERSPECTIVE

DISTALZ, A LABORATORY OF EXCELLENCE IN THE INTERNATIONAL RESEARCHCOMMUNITY DEVOTED TO ERADICATING ALZHEIMER'S DISEASE

The Institute

Research Report 2016 / institut pasteur de lille / 75

partners ofinstitut pasteur de lille

Supports

1, rue du professeur calmettebp 24559019 lille cedex

tél. +33 (3) 20 87 78 00

www.pasteur-lille.fr

Fondation privée

reconnue d’utilité

publique

give to the institut pasteur de lille: every effort counts

donations bequests

Sponsorship Solidarity events