Proposal for a USTH Thesis Supervisor's name : Michèle BOITEL USTH Thematic Group : Biotechnology - Pharmacology Status (prof., assistant prof., …) : Assistant Professor, HDR Laboratory : EA3900 BioPI-UPJV "Biology of Plant & Insect Website address : interactions" http://www.u-picardie.fr/labo/biopi/ Institution : Université de Picardie Jules Verne Website address : http://www.u-picardie.fr/ scientific domain of the research team: conception and studies of biotechnological processes for the production of pharmaceuticals from medicinal plants // key words : Plant biotechnology, secondary metabolite production, plant metabolomics, extraction of medicinal compounds from whole plants, in vitro and bioreactor cultures,hydroponics, GC-MS-MS, LC-MS-MS, MNR. Two major publications in the field proposed for the PhD : JOUSSE C; VU THI D, TRAN TLM, AL BALKHI MH, MOLINIE R, BOITEL-CONTI M, PILARD S, MATHIRON S, HEHN A, BOURGAUD F, GONTIER E, 2010 - Tropane Alkaloid Profiling of Hydroponic Datura innoxia Mill. Plants Inoculated with Agrobacterium rhizogenes. Phytochemical Analysis, 21 (1) : 118-127. AMDOUN R., KHELIFI L., ..., ASSAF-DUCROCQ C., GONTIER E. (2009). Influence of minerals and elicitation on Datura stramonium L. tropane alkaloid production: modelization of the in vitro biochemical response. Plant Science 177, 81-87. Website address of the personal page : 1°) http://www.u-picardie.fr/labo/biopi/ 2°) 3°) http://www.u-picardie.fr/html/Competences/Sante/Sante.html http://rootlines-tech.com/ 4°) 5°) http:// http://www.google.fr/url?sa=t&source=web&cd=3&ve Supervisor's email : email@example.com co-supervisor: firstname.lastname@example.org www. Description of the research work proposed for a PhD Title : Study of Lignan biosynthesis in roots and hairy roots of Linum plant species; development of a biotechnological process for anticancer podophyllotoxin derivatives production Subject : Context: Lignans are a large class of dimeric phenylpropanoids widely distributed in higher plants (Umezawa 2003). Lignan structures show considerable diversity paralleled by a wide spectrum of biological activities (Saleem et al.,2005). Approximately 3000 different structures of lignans and associated natural products such as neo-, sesqui-, and avonolignans have been listed in the Dictionary of Natural Products. These molecules have attracted considerable attention because of numerous pharmacological activities. Some of them have been developed into clinically approved therapeutics and others are considered as lead structures to new drugs (e.g., Apers et al., 2003; Lee and Xiao, 2003; Saleem et al., 2005). Due to the presence of the anti cancer agent podophyllotoxinin in Linum album (Weissetal.,1975), there was an increasing interest in investigation of Linum species for lignans. Furthermore, it has been reported that some Linum species accumulate arylnaphthalene lignans such as justicidinB which were found in in vitro cultures of Linum austriacum (Mohagheghzadeh et al., 2002), Linum lewisii, Linum altaicum (Konuklugiletal., 2007), Linum narbonense, Linum leonii (Vasilev et al., 2004) and Linum glaucum (Mohaghegh-zadeh et al., 2009). Arylnaphthalene glycosides were identified in Linum perenne cultivar Himmelszeltfl (Hemmatietal., 2007a). PhD program: Such a wide diversity of interesting lignans and derivatives in the Linum species leads us to propose an investigation on the potential of such plants to produce secondary metabolites with potent anti cancer activity. Then, based on the experience of BIOPI research unit in studying plant secondary metabolism, we propose to develop hairy root cultures (cultivated in bioreactors) of choosen Linum species in order to produce podophyllotoxin type metabolites whether i) directly using elicitation of the native biosynthetic pathway or ii) through the use of Linum usitatissimum lignans employed as precursors for further biotransformation. These studies will be conducted in parallel onto entire plants cultivated in soilless conditions (hydroponics & aeroponics) as parallel biomass and metabolism reference. This work will be conducted using metabolomics approach in order to generate phytochemical datas on secondary metabolism but also on primary metabolism modification as a function of plant lines and environmental conditions. Mass spectrometry will be used as major investigation method but MNR spectroscopy may also be used as necessary. Opportunity for the PhD candidate: Finally, this work will lead to academic knowledge concerning lignan derivatives metabolism but should also generate biotechnological methods for the production of anti cancer agents derivating from podophyllotoxin. Within the USTH project, this PhD subject will allow the development of a collaborative bridge between Vietnam and France for i) the biotechnological valorisation of plant diversity for the production of high value pharmaceuticals and ii) for further metabolomics studies devoted to pharmacology and biotechnology. The PhD candidate will acquire skills in biotechnology (in vitro culture, plant tissue culture, plant bioreactor, elicitation, biotransformation….) and in analytical biochemistry devoted to pharmaceuticals (metabolomics, GC-MS, LC-MS, statistical methods and softwares…). These competences will be of major interest for the USTH department of pharmacology-biotechnology (for teaching in the USTH Master and for the research activity within the UMI-USTH program). The candidate will also integrate the european network “COST Action: Plant Metabolic Engineering for High Value Products; approval n° FA1006” in which BIOPI is still integrated. This international dimension will help the candidate for his (her) further career. The candidate will integrate the BIOPI research group "root secondary metabolim" mainly composed of: Michèle Boitel, Séverine Schiltz, Rebecca Dauwe, Nathalie Julian-Pawlicky, Katiba Mezbreb, Jean-Claude Laberche, Michelle Lequart...) Key words Plant Biotechnology, secondary metabolites, anti cancer drugs, plant pharmaceuticals, Linum, metabolomics, lignan, podophyllotoxin, mass spectrometry. Expected collaborations in Vietnam M Boitel, E Gontier, JC Laberche will come at USTH VAST in Hanoi in April 2011 and will look for contacts with USTH VAST scientists in order to develop sustainable collaborations on plant metabolism study for the valorization of secondary compound with pharmaceutical interest. M Boitel, E Gontier, JC Laberche are experienced in collaboration with Vietnam: collaborations still exist with the Institute on Agronomy and Agroferestry of Thu Duc (Dr. PhD Tran Thi Le Mihn; email@example.com , and supervisors) and the Institute of Agronomy of Hanoi (Dr. PhD Vu Thi Dao, firstname.lastname@example.org, and supervisors). An agreement has been signed between the University of Picardie Jules Verne and the Institute of Agronomy of Hanoi. If a cosupervision is possible, please give the name and institution of the Vietnamese cosupervisor : The possibility of a co-supervision with Hanoi scientists (co-tutelle) will be determined in April 2011 at VAST USTH.