Françoise LENFANT / CORALIE FONTAINE

MODULATION OF THE OESTROGEN RECEPTOR ERα: VASCULAR, METABOLIC and ENDOCRINE DYSFUNCTIONS (ESTER)

Our work is focused on understanding the molecular and cellular mechanisms of actions of Estrogen Receptor ERα in its physiological vasculoprotective and metabolic preventive effects of estrogens and Selective Estrogen Receptors Modulators (SERMs). Four main axes are developed, in collaboration with clinicians at the CHU of Toulouse: 1) prevent apparition of aging-vascular diseases, 2) contribute to the development of new estrogenic molecules to improve the safety of oral contraception and of menopausal hormone therapy, 3) understand dialogue between estrogenic and circadian signaling, 4) develop translational research on an estrogenic dependent pathology: endometriosis.

JF. Arnal and F. Lenfant have been included in the Official Selection of the Prix Galien 2022 and 2023 in the “Research work” section.

Their work is honoured: the coronary artery risk of women is reduced by oestrogen hormones, but at the cost of certain risks. By better understanding their mechanisms of action, the work of Jean-François Arnal and Françoise Lenfant proposes a safer modulation of the estrogen receptor in medicine (contraception, menopause).

TEAM

Post-Doctoral researcher
Khrystyna BORIAK

Team leader

Françoise LENFANT

PhD, Director of research, Group leader

Career path

Françoise LENFANT received her PhD in Microbiology from the Institut National des Sciences Appliqués à Toulouse, in 1991. From 1991 to 1994, she worked as a post-doctoral fellow in the field of Molecular Biology at the University of California, USA, then in Toulouse in the field of reproduction and was recruited as a principal investigator at INSERM, Toulouse, in 1997. Since 2005, Francoise LENFANT is a Director of research at the INSERM U1297, working on modulation of Estrogen Receptor in medicine.

Main domains of expertise

Sexual steroids, Estrogen Receptor, reproduction, endothelium, breast cancer, in vivo models.

Email::francoise.lenfant@inserm.fr

Tél/Phone::+33 531224093

Co-Team Leader - Researcher

Coralie FONTAINE

CRCN (research fellow, normal class) at INSERM

Develops research on the impact of estrogen receptor (ER)a modulation on the arterial wall with implications for vascular pathologies such as atherosclerosis.

Career path
D. in biochemistry and molecular biology at the University of Lille (2002-2006), Postdoc at the University of Nice (2007-2008), joined the I2MC in Toulouse in 2008 and was recruited as a research fellow at Inserm in 2010.

Field of expertise
Nuclear receptor, estrogen, endothelium, in vivo approaches.

Email:Coralie.fontaine@inserm.fr

Tél/Phone:05 31 22 40 89

Reseachers

Jean-François ARNAL

Jean-Francois ARNAL, Professor of Physiology

Jean-François ARNAL is professor in Physiology at Toulouse 3 University of Medicine and at Toulouse University Hospital since 1997, after a doctorate in medicine (1990), and a doctorate in physiopathology (1993) followed with a post-doctoral internship at the ‘Emory University at Atlanta (1994). He led the team until 2019 studying the structure-function relationships for optimization of Estrogen Receptor Alpha (ERα) modulation in medicine, summarized in the review: Membrane and Nuclear ERα Actions: From Tissue Specificity to Medical Implications. Arnal JF, Lenfant F, Metivier R, Flouriot G, Henrion D, Adlanmerini M, Fontaine C, Gourdy P, Chambon P, Katzenellenbogen B, Katzenellenbogen J. Physiol Rev . 2017 Jul 1; 97 (3): 1045-1087. PMID: 28539435. He is a foreign member of the Royal Academy of Medicine of Belgium (2020). He collaborates with Mithra Pharmaceuticals on Estetrol (E4) in oral contraception He obtained the Lamonica Prize for Cardiology of the Academy of Sciences in 2019. He is also a professor in physiology in PACES / PASS and in the 2nd year of medicine and is co-responsible for the Master resaerch in physiopathology: from molecular to medical, and prepare future M.D. students in 2nd year of medicine at the INSERM School and at the ” MD-PhD training program ”. Videos M2 level: Role of estrogens in cardiovascular diseases – Jean-François ARNAL – Dec 2018 https://www.youtube.com/watch?v=C_Gq8xIWubM

Email:jean-francois.arnal@inserm.fr

Researcher

Marine ADLANMERINI

CRCN, INSERM researcher

Career path
Marine ADLANMERINI received her PhD in Physiology at the university of Toulouse (FR) in 2015. From 2016 to 2020, she worked as a post-doctoral fellow in the laboratory of Mitch Lazar in Philadelphie (USA) and then joined I2MC at Toulouse in 2021. She was recruited at the position of CRCN (tenured researcher) at the Inserm in Decembre 2021.

Main domains of expertise
Nuclear receptor (ER and REV-ERB), estrogen, circadian rhythms, metabolism, in vivo approaches.

Email:marine.adlanmerini@inserm.fr

Tél/phone:05 31 22 40 89

CLINICIAN

Elodie CHANTELAT

CLINICIAN

Xavier GAME

CLINICIAN

Florence TREMOLIERES

Endocrinologist, MD.PHD, PU-PH in Medical Gynecology

Career path

Doctorate in Medicine in 1989, speciality Endocrinology and Metabolic Diseases. Post-doctoral training (1989-1991) in the Department of Bone Mineral Metabolism (Pr. D.J. Baylink), University of Loma Linda (California – USA). University thesis in Developmental Biology at the University Paul Sabatier (Toulouse III) in 1995. Habilitation to direct research (HDR) in 2002. She joined Team 9 (Dr. Françoise Lenfant, Pr. Pierre Gourdy) of the I2MC in 2006 as a clinician. Head of department since 2011 of the Menopause Centre, the only university centre in France dedicated to menopausal women. Founding member (2009) and President of the Study Group on Menopause and Hormonal Aging (GEMVi) (2019). Member of the boards of the European Menopause and Andropause Society (EMAS) (2009-2015) and of the International Menopause Society (IMS) (2014-2018). Officer of the Palmes Académiques (2017).

Area of expertise

Study of the tissue consequences of estrogen deficiency states, particularly in terms of bone, cardiovascular and oncology in the post-menopause. Specialist in post-menopausal osteoporosis and metabolic bone pathologies.

She is a regular speaker at national and international congresses on the subjects of menopause and osteoporosis and is the author of more than 170 articles published in international or national referenced journals and of more than 15 book chapters.

CLINICIAN

Marie VALERA

Lecturer – Hospital practitioner

Career path

2005 : PhD in Dental Surgery. Paul Sabatier University (UPS) Toulouse III. 2005-2006: Master 2 Research. Mention Cellular and Integrated Physiology-Physiopathology.UPS Toulouse III. 2006-2009: University Doctorate in Cellular, Molecular and Integrated Physiopathology. INSERM U1048, I2MC. 2016 : Recruitment as Senior Lecturer/Hospital Practitioner.

Her current research focuses on understanding the pathophysiological mechanisms involved in the effects of estrogens on blood platelets and thrombosis in mouse models.

Area of expertise
Haematology, animal experimentation, microsurgery

Engineer

Mélissa BUSCATO

Engineer

Career path

Holder of a BTS BioAnalyses and Controls at the Saliège high school in Balma and an engineering degree in Sciences and Life of the Earth at the EPHE. She joined I2MC on a fixed-term contract in 2011.

She works as an engineer in the team on the study of vascular and metabolic effects of estrogens and SERMs.

Field of expertise
Animal experimentation, cellular and molecular biology, histology.

PhD Student

Adrien GARGAROS

PhD Student at INSERM

Adrien Gargaros’ project focuses on the study of estrogen receptors in endometriosis lesions and the implementation of a new model for studying the pathology.

Career path

Master of Biology and Health specializing in Physiopathology at the University of Toulouse (2020). Study engineer since 2021.

Areas of expertise

Cell and molecular biology, Cell culture, Imaging, Animal experimentation, Estrogen receptor

Email:adrien.gargaros@inserm.fr

Post-Doctoral researcher

Khrystyna BORIAK

Post-Doctoral researcher

Career path

Main domains of expertise

Email:khrystyna.boriak@inserm.fr

PhD Student / Clinician

Ariane WEYL

PhD Student / Clinician

Email:ariane.weyl@inserm.fr

ITA

Sylvie Nguyen

Technical staff

Email:sylvie.nguyen@inserm.fr

Assitant Engineer

Pauline AURIOL

Assitant Engineer

Email:pauline.auriol@inserm.fr

PhD Student

Perrine SINGLA

PhD Student

Cheminement de carrière

Principaux domaines d’expertise

Email:perrine.singla@inserm.fr

Doctorante

Faustine Darnaud

PhD Student

Email:faustine.darnaud@inserm.fr

PhD Student

Juline MARJOLLET

PhD Student

Email:juline.marjollet@inserm.fr

PhD Student / Clinician

Anna GOSSET

PhD Student / Clinician

Email:anna.gosset@inserm.fr

OPTIMIZATION OF ESTROGEN RECEPTOR MODULATION

Coordinators : Coralie Fontaine, Marine Adlanmerini, Marie-Cécile Valéra, Florence Tremolières, Jean-François Arnal et Françoise Lenfant

Using a combination of pharmacological approaches and the use of mouse models targeting the different sub-functions of ERα (nuclear versus membrane-initiated signaling), our objectives are to optimize the activation of ERα to develop new therapeutic strategies to optimize hormonal therapies used in various pathologies in women (treatment of menopausal symptoms, breast cancer, endometriosis?). We are contributing to these developments through partnerships with a Belgian Biotech (Mithra) which is developing estetrol, a fetal estrogen and big pharmas (Pfizer).

Look on the BD In Sciences on page 46 (Estetrol: la fine fleur des oestrogènes): https://www.calameo.com/read/0051544509cf52b7059c6

IMPACT OF AGING ON ARTERIAL PROTECTION BY ESTROGENS

Coordinators : Coralie Fontaine, Jean-François Arnal

Women are protected against cardiovascular risk compared to men until menopause. This protection conferred by endogenous estrogens during the period of genital activity can be extended with estrogen supplementation when hormonal treatment is administered early after the onset of menopause. Our goal is to understand the loss of arterial protection by estrogens during aging by studying the impact of age on the signaling of Estrogen receptor ERα signaling in arterial wall.

This project is financed by Fondation de France, ANR (ArtER), and Région Occitanie/EU 2024-FEDER-HUM (conducted in partnership with the company Physiotim (Castres, France).

DIALOGUE BETWEEN ESTROGENIC AND CIRCADIAN SIGNALING

Coordinators : Marine Adlanmerini, Coralie Fontaine

Estrogen receptor alpha (ERa), the major mammalian estrogen receptor, is expressed with a large circadian rhythm. Furthermore, estrogen signaling is known to regulate several circadian functions in women, but also in men. By exploring the hypothesis that ERα may act as a time donor capable of driving circadian metabolism, our team aims to determine the molecular mechanisms and physio(patho)logical implications of the dialogue between estrogen and circadian signaling toward chronotherapeutic strategy in menopausal women and prevention of cardiovascular diseases.

This project is financed by ANR (Helios) and ANRJC (CirER).

THE MECHANISM OF ACTION OF OESTROGENS IN ENDOMETRIOSIS

Coordinators : Elodie Chantalat, Françoise Lenfant

Endometriosis, present in 10% of reproductive-aged women, is an estrogen-dependent, chronic inflammatory gynecologic disease that is characterized by the presence of endometrial tissue outside the uterus and induced pelvic pain, infertility and impaired quality of life. Our project proposes a multidisciplinary approach to better understand ERα mechanisms of actions in endometriosis, using human tissue biopsies, peritoneal fluid and development of a platform of endometrial organoids derived from these tissues. The ultimate goal is to propose new therapeutics to control the endometriotic process without inducing systemic estrogen deprivation and its long-term deleterious consequences.

Project performed in close collaboration with CHU-Toulouse- Service of Gynecological Surgery with the financial support from EndoFrance Association, the Région Occitanie-GRAINE- EndoTREAT,( in partnership with Urosphere), ANR-EDISON and the PEPR-Santé des femmes.

RECENT PUBLICATIONS

Reprogramming of endothlial gene expression by tamoxifen inhibits angiogenesis and ERa-negative tumor growth. Fébrissy C, Adlanmerini M, Péqueux C, Boudou F, Buscato M, Gargaros A, Gilardi-Bresson S, Boriak K, Laurell H, Fontaine C, Katzenellenbogen BS, Katzenellenbogen JA, Guillermet-Guibert J, Arnal JF, Metivier R, Lenfant F. Theranostics. 2024 Jan 1;14(1):249-264. doi: 10.7150/thno.87306. eCollection 2024. PMID: 38164151 Free PMC article. Pubmed

Special issue on non-genomic actions of nuclear receptors: An evolutionary and physiological perspective. Arnal JF, Fontaine C, Adlanmerini M, Lenfant F. Mol Cell Endocrinol. 2023 Mar 15;564:111884.doi:10.1016/j.mce.2023.111884. Epub 2023 Feb 3. PMID: 36739891. Pubmed

The different natural estrogens promote endothelial healing through distinct cell targets. Davezac M, Zahreddine R, Buscato M, Smirnova NF, Febrissy C, Febrissy C, Laurell H, Gilardi-Bresson S, Adlanmerini M, Liere P, Flouriot G, Guennoun R, Laffargue M, Foidart JM, Lenfant F, Arnal JF, Métivier R, Fontaine C. JCI Insight, 2023. Pubmed

Loss of function of the maternal membrane oestrogen resceptor ERa alters expansion of trophoblast cells and impacts mouse fertility. Rusidzé M, Faure MC, Sicard P, Raymond-Letron I, Giton F, Vessieres E, Prevot V, Henrion D, Arnal JF, Cornil CA, Lenfant F. Development. 2022 Oct 1;149(19):dev200683. doi: 10.1242/dev.200683. Epub 2022 Oct 13. PMID: 36239412. Pubmed

Tamoxifen Accelerates Endothelial Healing by Targeting ERα in Smooth Muscle Cells, Zahreddine R, Davezac M, Smirnova N, Buscato M, Lhuillier E, Lupieri A, Solinhac R, Vinel A, Vessieres E, Henrion D, Renault MA, Gadeau AP, Flouriot G, Lenfant F, Laffargue M, Métivier R, Arnal JF, Fontaine C.,Circ Res, 2020. Pubmed

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