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Reproductive Biology Early Research Training

Final Report Summary - REPRO-TRAIN (Reproductive Biology Early Research Training)

REPRO-TRAIN, “Reproductive Biology Early Research Training” is a Marie Curie Initial Training Network funded by the European Commission under the 7th Framework Programme (FP7-PEOPLE-2011-ITN, PITN-GA-289880). It is composed of 7 strong academic research groups and 2 pharmaceutical companies from 6 different European countries: France, Italy, Netherlands, Germany, UK and Spain. The network started on January 1st 2012 and ended on December 31st 2015.
REPRO-TRAIN integrated a research environment involving complementary frontier “omic” approaches in male reproductive biology for the first time with the aim of identifying novel human fertility genes and the gene networks that are deregulated in the infertile and malignant testis.
We have delivered a high standard of multidisciplinary network-wide training to 10 Early Stage Researchers (ESRs) and 4 Experienced Researchers (ER) who performed studies in genetics and epigenetics, molecular male reproductive medicine, molecular and structural biology and biotechnology. This learning environment was implemented with hands-on training in cutting-edge technologies relevant to current molecular-genetic and medical research together with a Personnel Career Development Plan and complementary transferable skills.

Overall objectives
1. To provide a comprehensive interdisciplinary training programme for early stage researchers in state-of the-art male Reproductive Biology and Andrology allied to Medicine.
2. To overcome historical fragmentation in the field of spermatogenesis and Andrology research by integrating and implementing different disciplines in ongoing research projects in male Reproductive Biology and Medicine.
3. To develop and implement systems biology based approaches (genomic, proteomic, transcriptomic, epigenetic and metabolomic) to boost the acquisition of fundamental knowledge in the field of male Reproductive Biology and Medicine.
4. To develop novel clinical and industrial applications of this knowledge by potentiating the synergies between the different consortium members and their private sector partners.

Specific scientific objectives
1. Characterisation of the sperm nuclear proteome in human and in model organisms. Identification of the function and epigenetic role of the novel proteins identified in model systems, with particular reference to models of infertility and to the infertile patient.
2. Apply Genome-Wide Association Studies (GWAS), Exome Sequencing (ES) and Semen Transcript Profiling (STP) of infertile patients to identify novel gene networks and candidate genes involved in male fertility and infertility and in patients with prostate cancer. Potential semen-based diagnostic for exfoliated prostatic cells and prostate cancer is one possible outcome of a non-invasively mapped testis gene expression profile.
3. Characterisation and function of the proteins encoded by novel identified genes through protein localisation (IF studies), epigenetic mapping of the nuclear proteins, and animal model studies (knock-out/knock-in).
4. Characterisation of the epigenetic constitution of the sperm cell in human and in model organisms is planned alongside the identification and analysis of the gene sequences associated with the differentially packaged regions of mature sperm chromatin with the identification of anomalies in these parameters assessed in infertile patients.
5. Development of biomedical applications spinning-off the fundamental knowledge and translational research results derived from the previous objectives.

Training offered
Consistent with the major intended goal of this ITN, the main training received by the fellows was the hands-on training on research together with the seven training workshops organised in three sets. The first set of training workshops was held in June 2013 in Barcelona, Spain during the first period of the project. It was composed of four workshops: the Sperm Phenotypic Assessment workshop (W1), the Transcriptomics workshop (W4), the Proteomics workshop (W5) and the Epigenetics workshop (W6). The second set of training workshops was held from the 31st March until the 4th April 2014 inMarburg, Germany. It consisted of two workshops. The Model Systems in Reproductive Medicine and Andrology workshop (W2) and the Reproductive Genetics and Genomics workshop (W3). Several hands on training sessions were programmed during the workshop weeks together with oral sessions that were open to the general audience outside the consortium. The Biomedical Application and Transfer of Knowledge workshop (W7) was organized from the 6th to 10th July 2015 inBarcelona, Spain. The fellows received training in IPR, technology transfer, overview of biotech companies, starts-up and biotech research. The fellows also attended specific courses, seminars and conferences to broaden their knowledge in their field of research. Additionally, the fellows were seconded to other laboratories within the consortium to complement their training. All the recruited ESRs joined Doctorate programs in their respective institutions to obtain a PhD title during 2016.

Main results
Genomic studies involving the analysis of X chromosome-linked CNVs have led to the discovery of a significantly higher duplication load in patients in respect to normozoospermic controls, suggesting a possible link between genomic instability and higher morbidity/mortality in infertile men.Exome analysis with Next generation Sequencing has been successful in identifying both X-linked and autosomal gene mutations in familial cases of infertility.In addition, a large multicentre study it was possible to give a definitive answer to the debated issue on the association of AZF deletions with SHOX haploinsufficiency.
From a proteomic point of view, many proteins were identified as associated to human sperm motility alterations, cryo-injury and embryo quality. Also changes in the sperm proteome associated with sperm capacitation, acrosome reaction,in vitro matured human sperm cells and in the sperm proteome of offspring and grand-offspring of a mouse model of paternal-induced obesity.
From an epigenetic point of view, important knowledge on the epigenetic drivers of male germ cell stage-specific gene expression programs and epigenetic determinants of histone-to-protamine replacement during late spermatogenesis has been generated. This knowledge also allows us to investigate the involvement of all these mechanisms in male infertility. Thanks to this work we are in a position to consider the possible transmission of epigenetic traits to the offspring and to establish criteria for the “epigenetic quality” of sperm cells before their use in ART. Additionally, important results have also been obtained in the study of the effect of inhibitors of epigenetic targets in spermatogenesis and male reproductive cancers.
Transcriptomic projects generated transcript profiles from clinically relevant samples (sperm and seminal plasma) and model systems in order to identify genes involved in male infertility and prostate / testis cancer markers.Candidate biomarkers for prostate cancer as well as successful sterilization and post-surgical trauma were identified.
A total of 14 research articles in international peer-reviewed journals and 22 manuscripts in preparation to be published in 2016 is the main output at the end of the project.

• To bring together a critical mass of research laboratories essential to make a contribution to the state of the art in reproductive biology and andrology and end users of these new research that are active in the development of biomedical applications.
• To promote the training and/or transfer of knowledge in Reproductive Biology and Andrology
• To improve attractiveness of science to researchers
• To improve attractiveness of Europe to researchers

International dissemination
1. The 5th Florence-Utah Symposium on the Genetics of Male infertility, held from the 19th to the 21st September 2013 in Florence, included a REPRO-TRAIN session in its program.
2. European Congress of Andrology, 15-17 October 2014, Barcelona, Spain. Reprotrain fellows participated in the poster sesión
3. ESHRE Annual Meeting, 29th June-2 July 2014, Munich, Germany. Pre-congress Course 2: Treating the man with evidence based medicine. Session: The latest findings from the REPROTRAIN consortia.
4.“Frontiers in Male Infertility research” Open sessions of the Reprotrain Final Meeting, 12th-13th November in Barcelona, Spain

Website and contact details
The REPRO-TRAIN website ( provides more detailed information on REPRO-TRAIN beneficiary institutions, research groups, fellows, specific research projects, output, important scientific and training events and contact information. Since the website was active on the 20th May 2012 it has received more than 93,000 visits from 14,700 visitors in 145 different countries (data obtained from Google Analytics, Jan 2016).
Email contact:
Coordinator: Dr. Rafael Oliva,
Project Manager: Dr. Montserrat Codina,