ESR Project 1
Mitochondrial function, the telomere system and epigenetic programming of bovine oocytes
Scientist-in-charge: Associate Professor Trudee Fair, University College Dublin, Ireland
During oogenesis, tightly orchestrated molecular and structural modifications, fundamental to successful development, occur in the nucleus and cytoplasm of oocytes. There is continual cross-talk between the nucleus and cytoplasm; published models include crosstalk between epigenetic regulation and telomere biology, epigenetic regulation and mitochondrial function, and telomere biology and mitochondrial function. Although not yet developed, a fully integrated model might account for many processes associated with oocyte quality and developmental programming or indicate checkpoints for potential endogenous/exogenous environmental manipulation. The aim of this project is to characterize the crosstalk between epigenetic regulation and telomere biology, epigenetic regulation and mitochondrial function, and telomere biology and mitochondrial function of bovine oocytes.
ESR Project 2
Progesterone (P4) Regulation of Oocyte Growth & Maturation in Cattle
Scientist in charge: Associate Professor Trudee Fair, University College Dublin, Ireland
Cumulus Oocyte Complexes dynamically express both nuclear and membrane-bound progesterone receptors during maturation. Furthermore, the expression pattern is modulated in the presence of LH, FSH or P4. Inhibition of P4 synthesis or blocking the activity of the nuclear Progesterone Receptor during oocyte in vitro maturation, disrupts normal maturation and is associated with reduced oocyte competence. The aim of this project is to identify P4-mediated molecular and cellular pathways involved in bovine oocyte growth and maturation and to determine the key pathways and stress responses associated with poor oocyte quality and embryo mortality in a suboptimal P4 signalling environment.
ESR Project 3
Physiological culture systems to access untapped ovarian reserves for improving reproductive efficiency
Scientist in charge: Associate Professor Alberto Maria Luciano, University of Milan, Italy
The cohort of growing oocytes within preantral secondary follicles is a potentially larger source of oocytes compared with those in antral follicles. However, growing oocytes are still undergoing cytoplasmic changes, transcription and chromatin modifications that are essential for the control of gene expression and are required for the establishment of a proper maternal specific genomic imprinting and global methylation patterns. These processes are crucial for the attainment of the full embryonic developmental competence of a functional gamete.The project aims at determining the critical constituents of the ovarian microenvironment that orchestrate oocyte differentiation from preantral-to-antral stage of follicle development, leading to the definition of a multi-step preantral culture strategy that closely mimics the physiological environment.
ESR Project 4
Optimisation of in vitro follicle culture methods in mice to improve developmental competence and offspring health
Scientist in charge: Professor Ellen Anckaert, Vrije Universiteit Brussel, Belgium
In vitro 3D-follicle culture systems, preserving the spatial configuration of the follicle, offer great potential to improve the developmental capacity of cultured oocytes, but are insufficiently optimized. Essential components of the ovarian extracellular matrix (ECM) have been identified and will be applied to early preantral In vitro follicle culture (IFC) systems to create an interactive 3D oocyte culture system. The aim of this project is to create a physiological environment which facilitates appropriate oocyte differentiation from preantral to antral follicle stage using mouse and bovine models. Oocyte meiotic and developmental competence and long-term health of adult offspring will be monitored.
ESR Project 5
Impact of the sub-cortical maternal complex on epigenetic programming of oocytes
Scientist in charge: Dr Gavin Kelsey, Babraham Institute, Cambridge, UK
The sub-cortical maternal complex (SMC), a multi-protein structure of the mammalian oocyte, orchestrates several essential cellular processes during the oocyte-to-embryo transition, including spindle assembly, chromosome alignment and symmetric cell division in cleavage-stage embryos. The aim of the project is to determine whether SMC defects cause failures in methylation establishment in oocytes, what genomic features are most susceptible, and the mechanisms responsible.
ESR Project 6
Mitochondrial-driven splicing deregulation: New mechanism to explain the loss of competence in aged oocytes
Scientist in charge: Dr Rita Vassena, Clinic Eugin, Barcelona, Spain (Enrolment in Universitat Autonoma De Barcelona)
The oocytes of women of 35 years and older i.e.,advanced maternal age (AMA),have a higher rate of meiotic aneuploidy, meiotic spindle assembly defects, and decreased mitochondrial activity. Alternative Splicing deregulation has been linked to ageing; recent work has associated mitochondrial dysfunction to alternative splicing deregulation in cellular models. It is likely that a similar mechanism acts in AMA oocytes, where the decreased mitochondrial activity might affect the oocyte developmental competence through the modulation of RNA alternative splicing. The aim of the project is to untangle the relationship between alternative splicing deregulation, reduced mitochondrial metabolic activity and spindle integrity in AMA oocytes.
ESR Project 7
Somatic signals regulating mRNA translation in mammalian oocytes
Scientist in charge: Dr Federica Franciosi, University of Milan, Italy
During oocyte maturation transcription is repressed and cellular functions, comprising meiotic progression and reprogramming of the genome to totipotency, are mainly regulated by the timely translation of maternal mRNA accumulated during oocyte growth. Recent studies show that the follicular/cultural environment affects oocyte developmental competence by acting on the program of maternal mRNA translation, through the activation of the PI3K/AKT pathway in the oocyte. However, the intercellular signalling linking the somatic and germline side of this cascade has not been elucidated. The aim of the project is to dissect the ability of signals originating in the follicular cells, transduced to the oocyte in response to the ovulatory stimulus, to affect the oocyte translational program.
ESR Project 8
Identification of signalling factors during bovine oocyte maturation
Scientist in charge: Professor Ann van Soom, University of Ghent
The addition of oocyte-secreted factors (OSFs) to in vitro maturation medium has shown potential to improve the developmental competence of oocytes in different animal models, suggesting immature oocytes from small antral follicles are deficient in OSFs. Oocyte and cumulus cell secreted factors such as ncRNAs and proteins may play a role in oocyte epigenome remodeling, chromatin integrity, maternal RNA translation and cytoplasmic acquisition of competence. The aim of the project is to identify candidate soluble molecules that will be added to in vitro maturation conditions to improve oocyte development and oocyte quality.
ESR Project 9
Development of a Machine Learning platform to support assisted reproductive technologies
Scientist in charge: Dr Josep Lluís Arcos. Host institution Cientificas (CSIC): Agencia Estatal Consejo Superior De Investigaciones (Enrolment in Universitat Autonoma De Barcelona)
It is often difficult to distinguish between epigenetic aberrations associated with infertility and those induced by assisted reproductive technologies (ART). Routine robust safety checkpoints for ovarian cortex and gamete storage techniques are not yet established for ART. Artificial Intelligence training on EUROVA research and clinical datasets could lead to the development of case specific diagnostic and therapeutic targets of oocyte development and survival. The aim of this project is to design a software platform, based on Artificial Intelligence and Machine Learning for analysis and validation of ART data to support research and clinical exploitation of data analysis pipelines, which can be used for patient focused interventions and for standardization of ART culture systems.
ESR Project 10
Proteomic profiling of AMA oocytes: from basic biology to improving fertility in aged women
Scientist-in-charge: Dr Rita Vassena, Clinica Eugin, Barcelona (Enrolment in UCD)
The oocytes of women of 35 years and older i.e.,advanced maternal age (AMA), have a higher rate of meiotic aneuploidy, meiotic spindle assembly defects, and decreased mitochondrial activity. Proteomic profiling of young and old oocytes could provide valuable information on the differential expression of proteins in the aged oocyte. The aims of this project are to identify changes in the proteome of oocytes induced by aging, to determine the potential of candidate proteins to rescue the aged phenotype of bovine AMA-like oocytes, and to investigate the potential application of an AMA oocyte rescue strategy to IVM in a clinical setting.
ESR Project 11
Replication of in vivo maturation environment in vitro to reduce epigenetic and chromosomal aberrations
Scientist-in-charge: Professor Ann van Soom, University of Ghent, Belgium
Growing oocytes undergo modifications that are essential for the control of gene expression and are required for the establishment of a proper maternal specific genomic imprinting and global methylation patterns, processes crucial for the attainment of their full embryonic developmental competence. In vitro follicle culture (IFC) systems that mimic the physiological environment and facilitate appropriate oocyte differentiation from preantral to antral follicle stage will allow the use of this cohort of oocytes in assisted reproduction therapies. However, extensive improvement and validation of IFC systems are required before they can be applied to clinical use.The aim of this project is to develop a 3D co-culture system in bovine. The influence of different in vitro maturation conditions (3D, vesicles, temperature control) on epigenetic and chromosomal aberrations in bovine zygotes and cleavage stage bovine embryos will be investigated.
ESR Project 13
Development and safety analysis of optimized in vitro maturation in presence of oocyte-secreted factors (OSF)
Scientist-in-charge: Professor Ellen Ankaert, Vrie Universitet Brussel, Belgium
Conventional patient in vitro fertilization protocols involve hormone stimulation, thus patients at risk of ovarian hyperstimulation syndrome, require alternative assisted reproduction strategies, such as in vitro maturation (IVM). There is aneed to improve IVM conditions for human assisted reproduction. The addition of oocyte-secreted factors (OSFs) to IVM medium has shown potential to improve the developmental competence of oocytes in different animal models. The aim of this project is to characterize the meiotic competence of human oocytes following supplementation of IVM with novel OSF, Cumulin5 (heterodimer of GDF-9 and BMP-15); (2) To assess the quality of resulting oocytes at the molecular level. Genome-wide methylation maps and transcriptomic profiles will allow marker identification for use in future optimization studies to select culture protocols with minimal epigenetic interference.
ESR Project 14
Translational research for developing ART for endangered mammals
Scientist-in-charge: Professor Thomas Hildebrandt, Leibniz Institute for Zoo & Wildlife Research (Enrolment in FUB)
The family Rhinocerotidae is under grave threat of extinction; three of the five extant species are listed as critically endangered (Sumatran, Javan, and Black Rhinoceros). Female individuals of the rhino species develop severe reproductive pathologies if they do not get pregnant. The loss of uterine integrity combined with pregnancy failure precedes deterioration of oocyte quality, ART offers a window of opportunity to rescue the genetic resources of critically endangered rhinos by transferring IVP embryos into related or subspecies healthy surrogates. The aim of this project is to develop novel ART strategies that can be translated into practical conservation tools, serving as a blueprint for saving critically endangered mammalian species from extinction.
ESR Project 15
Optimizing conditions for freezing and transplantation of human ovarian tissue
Scientist-in-charge: Professor Claus Yding Andersen, RegionH, Rigshospitalet, Denmark
Transplantation of thawed ovarian tissue is currently the only available fertility preserving option for pre-pubertal girls and young women who cannot delay gonadotoxic treatment. However, almost 70% of follicles do not survive post transplantation and pregnancy rates are low. Antioxidants have been shown to reduce oxidative stress. The aim of this project is to identify the most effective antioxidant, the dosage and optimum stage of administration including transplantation of ovarian tissue in an immune privileged environment, during short and long term xenotransplantation, required to enhance follicle function and survival in frozen-thawed ovarian tissue after transplantation to restore fertility.
ESR Project 17
The role of ROS during oogenesis
Scientist-in-charge: Associate Professor Valentina Lodde, University of Milan, Italy
Reactive oxygen species (ROS) have always been regarded as the ones which are wrongdoers, but recent studies have uncovered the importance of ROS in many physiological processes as second messengers. Moreover, it is emerging that ROS have a precise function during animal development. However, little is known on the specific physiological function of ROS in mammalian oogenesis as well as in the developing embryo as well as on the specific contribution of the maternal ovarian compartment. This project aims at dissecting the putative physiological function of ROS during oogenesis, and precisely at critical stages of oocyte maturation function.