INSERM 

Description of the legal entity:

Inserm is a public scientific and technological institute which operates under the joint authority of the French Ministries of Health and Research. The institute is dedicated to biomedical research and human health, and is involved in the entire range of activities from the laboratory to the patient’s bedside. Inserm brings together 15,000 researchers, engineers, technicians, and administrative staff around one common goal: to improve the health of all by advancing knowledge of life and disease, innovation in treatment, and public health research.

The PI laboratory (http://www.i2mc.inserm.fr/index.php/fr/equipes-de-recherche/equipe-13) is located in the Institute of Cardiovascular and Metabolic Diseases (I2MC) created in 2011 by Inserm. The research activity focuses on metabolic, cardiovascular and renal diseases. The main feature of I2MC is the gathering of basic scientists together with clinicians working on metabolic risk factors (obesity, diabetes and dyslipidemia) and their cardiovascular complications (thrombosis, atherosclerosis, cardiac and renal failure).

The laboratory headed by Dr Garmy-Susini studies molecular regulations of (lymph)angiogenic factors in vascular pathologies. It developed research axes in the field of gene expression control in response to stress and in pathophysiology of the lymphatic system, connected to therapeutic axes of gene therapy of ischemic heart disease and lymphedema. The main objectives of the lab are to 1/identify the pathophysiology of the lymphatic system in lymphedema, 2/characterize regulation of lymphangiogenesis-related gene expression in stress conditions (hypoxia, ER stress…), and 3/develop innovative therapies to restore lymphatic flow to improve healing in ischemic heart and in lymphedema.

As scientific coordinator, INSERM will participate to all the basic science work packages. They will provide tools for each partner and they will coordinate the scientific project.

Curriculum Vitae:

Prof. Barbara Garmy-Susini (Female): PI with expertise in vascular diseases associated with the lymphatic and the blood vascular systems. H-index = 19, selected awards: Jean-Paul Binet scientific price from the Fondation pour la Recherche Médicale (FRM) 2017; California Breast Cancer Research Program Award 2004.

Dr. Anne-Catherine Prats (Female): Large expertise in gene therapy and molecular biology. H-index = 36 (Scopus), awards: 2015 : Medal of « Chevalier de la Légion d’Honneur », 2009 : Award of Toulouse mayor “les Lauriers de la Recherche”, 2003 : Award of the « Concours régional de l’Innovation en Midi-Pyrénées », 2001 : Medal of « Chevalier de l’Ordre National du Mérite ». 2000: Inserm award for therapeutic research.

Dr Florence Tatin (Female): Expertise in developmental biology of the lymphatic system. H-index = 13, Permanent position at Inserm, previously postdoctoral fellow in partner 4 (Makinen) lab.

Inserm Main tasks in the project

Coordinator of the project

Inserm is participating in all WPs except WP7 and will contribute to the following tasks

• WP1: Effect of photon/proton radiation on the lympatic endothelium in vivo ( Tasks 1.2) and Effect of chemotherapy on the lymphatic function (Tasks 1.4)
• WP2: Mouse and tissue architecture analysis (Task 2.1 and 2.2), Gene expression analysis (Task 2.3)
• WP3: Inserm is WP leader, Adipose tissue function in lymphedema (Task 3.1)
• WP4: Lipidomic analysis of resolving in lymphedema (Task 4.1), Effect of lipid meidators on the lymphatic endothelium and trafficking of immune cells (Task 4.2), Effect of the knock-down of lipid enzyme synthesis on the lymphatic function (Task 4.3)
• WP5: design of the molecular biology tools (Task 5.1), knockdown of therapeutic target in vitro (Task 5.2), Overexpression of therapeutic target in vitro (Task 5.3)
• WP6: Production of lentivectors and LentiFlash (Task 6.1), Validation of biodistribution and toxicity in preclinical models (Task 6.2)Validation of biological activity in preclinical models (Task 6.3)
• WP8, as coordinator of the project Inserm is responsible for the management of the consortium assisted by a project manager from Inserm Transfert.

WP9 Inserm will coordinate all dissemination and communication activities and will be responsible for the public Website and organization of the final TheraLymph international conference.

List of up to 5 relevant publications, and/or products, services (including widely-used datasets or software), or other achievements relevant to the  call content

• Morfoisse F. PhD¹*, Tatin F. PhD ¹*, Chapût B. MD², Therville N.³, Vaysse C. MD ⁴, Métivier R. PhD ⁵, Malloizel-Delaunay J. MD ⁶, Pujol F. ¹, Godet AC. ¹, De Toni F. PhD¹, Boudou, F. ¹, Grenier k. ⁷, Dubuc D. ⁷, Lacazette E. PhD ¹, Prats AC. PhD ¹, Guillermet-Guibert J. PhD ³, Lenfant F. PhD ¹, Garmy-Susini B. PhD^1#“Lymphatic vasculature requires estrogen receptor alpha signaling to protect from lymphedema”. Arterioscler Thromb Vasc Biol. 2018 Apr 12.

• Renaud-Gabardos E, Tatin F, Hantelys F, Lebas B, Calise D, Kunduzova O, Masri B, Pujol F, Sicard P, Valet P, Roncalli J, Chaufour X, Garmy-Susini B, Parini A, Prats AC. « Therapeutic Benefit and Gene Network Regulation by Combined Gene Transfer of Apelin, FGF2, and SERCA2a into Ischemic Heart.» Mol Ther. 2018 Mar 7; 26(3):902-916.

• Florence Tatin¹, Edith Renaud-Gabardos¹, Fransky Hantelys¹, Anne-Claire Godet¹, Francoise Pujol¹, Florent Morfoisse², Denis Calise³, Fanny Viars⁴, Philippe Valet¹, Bernard Masri¹, Anne-Catherine Prats¹ and Barbara Garmy-Susini¹ « Apelin modulates pathological remodeling of lymphatic endothelium after myocardial infarction. » JCI Insight June 2017.

• Morfoisse F, Tatin F, Hantelys F, Adoue A, Helfer AC, Cassant-Sourdy S, Pujol F, Gomez-Brouchet A, Ligat L, Lopez F, Pyronnet S, Courty J, Guillermet-Guibert J, Marzi S, Schneider RJ, Prats AC, Garmy-Susini « Nucleolin promotes heat shock-associated translation of VEGF-D to promote tumor lymphangiogenesis.» Cancer Res. 2016 Jun 8.

Florent Morfoisse, Anna Kuchnio, Clement Frainay, Anne Gomez-Brouchet, Marie-Bernadette Delisle, Stefano Marzi, Anne-Catherine Helfer, Fransky Hantelys, Francoise Pujol, Julie Guillermet-Guibert, Corinne Bousquet, Mieke Dewerchin, Stephane Pyronnet, Anne-Catherine Prats, Peter Carmeliet, Barbara Garmy-Susini. “Hypoxia induces VEGF-C expression in metastatic tumor cells via a HIF-1a-independent translation-mediated mechanism”. Cell Reports. 2014 Jan 16.

List of up to 5 relevant previous projects or activities, connected to the subject of this proposal

• Toulouse Cancer Sante Foundation – CHEMOLYMP, 100KEUR (2016-2019), PI
• National Institute of Cancer, INCA, 700KEUR (2015-2019), co-PI (4PI)
• National Agency for Research, ANR, 700KEUR (2018-2021), PI
• Regional FEDER UE, 300KEUR (2019-2021), PI
• Research association for cancer ARC, 50KEUR (2018-2020), PI

Infrastructure and/or major items of technical equipment

Animal care SPF facility CREFRE (in vivo imaging systems for live whole-body luminescence imaging, near-infrared imaging, high frequency ultrasound)

• I2MC offers scientists a diverse set of competence through its core facilities:
• Transcriptomics: single cell RNAsequencing
• Imaging: Confocal Microscop Zeiss LSM780, video-microscopy Wide Fiel Zeiss Cell-Observer, Super-resolution Microscopy with the Zeiss ELYRA PS
• Bioinformatics
• Lipidomics: relative and absolute quantification of lipids in various biological samples (fluid, cells, tissues…) by MS (GC-QqQ TSQ 8000 (Thermo), LC-QqQ 6460 (Agilent))
• Cytometry: Analyzer LSR Fortessa, Cell sorter: Influx (BD Biosciences)
• Histology
• Functional Biochemistry

Collectively, these facilities are run by 18 staff members that each strive to make available their unique skills and experience to the Institute.

Operational capacity

Fully operational