Award details

Bilateral BBSRC-FAPESP: Understanding novel conceptus-maternal communication is the key to improving pregnancy outcome in cattle.

Reference	BB/R017522/1
Principal Investigator / Supervisor	Professor Niamh Forde
Co-Investigators / Co-Supervisors
Institution	University of Leeds
Department	School of Medicine
Funding type	Research
Value (£)	558,449
Status	Completed
Type	Research Grant
Start date	02/10/2018
End date	30/09/2022
Duration	48 months

Abstract

Livestock farming supports the economic livelihood and food security of almost 1.3 billion people worldwide. One factor affecting the economic efficiency and sustainability of beef and dairy farming is poor reproductive outcome associated with embryo mortality. The majority of pregnancy loss occurs in the first three weeks and some of this loss can be attributed to dysfunction in communication between the embryo and the maternal environment. The endocrinological communication between the mother and the embryo (maternally-derived progesterone and the conceptus-derived pregnancy recognition signal Interferon Tau) have been well described. Novel non-endocrinological cross-talk between the conceptus and the mother, in the form of extracellular vesicles (EVs), has been less well described. This novel mode of conceptus-maternal communication may be the key to the step change we are seeking in improving agricultural efficiency. This proposal will address how EVs contribute to conceptus-maternal cross talk by investigating the composition of EVs derived from embryos with different developmental potential (high quality, in vivo embryos: intermediate quality, in vitro embryos; low quality, cloned embryos). The components of EVs which are incorporated into the endometrium will be determined by exploiting the sub-species sequence differences in transcript between Bos taurus (embryos) and Bos indicus (maternal environment). Analysis of how components of these EVs affect endometrial function will be determined in vitro. Differential fluorescent labelling of a membrane protein that encodes EVs in cloned embryos derived from a male and female lines will determine what conceptus-derived EV components get into maternal circulation and how these differ between conceptuses of different sexes. Collectively this will enhance our fundamental understanding of what contributes to early pregnancy success and will generate novel targets for manipulation to overcome early embryonic loss.

Summary

We know that Agriculture and Food security are of critical importance if we are to feed an increasing population with reduced resources. One factor that greatly affects the economic sustainability of both beef and dairy farming is the length of time it takes for either heifers or cows to establish and maintain successful early pregnancy. Increasing fertility in dairy and beef cattle can improve agriculture efficiency with a long term decrease in agriculture impacts worldwide. A major source of pregnancy loss in cattle occurs in the first 3 weeks of pregnancy and the question of when exactly this embryo loss occurs is unknown. What we do know is that successful communication between the embryo and the maternal uterine environment is crucial for successful early pregnancy. There are three key interactions that need to occur 1) the hormone progesterone needs to act on the endometrium (the tissue that lines the inner part of the uterus) to provide a suitable environment to host the embryo, 2) the embryo must undergo a rapid period of growth which is only possible in the uterus i.e. we cannot recapitulate this in the lab and 3) the conceptus must successfully signal its presence to the mother to sustain early pregnancy. Over the last number of years my work has focused on using a specific type of technology to help address the question of how the uterine environment and the conceptus (which is the embryo proper that forms the calf and the extra-embryonic membrane which forms the placenta) interact with one another. The technologies I have use have focused on transcriptomics and proteomics. Instead of investigating how one gene or protein changes in a given condition e.g. in early pregnancy these technologies allow us to investigate how the expression of lots of genes and/or proteins change in early pregnancy. This gives us a much broader picture of what is occurring both during successful early pregnancy, but also when early pregnancy loss occurs. The main focus of my research has been on 1) the role that a specific hormone progesterone plays in providing a good or insufficient uterine environment to promote successful early pregnancy 2) how the maternal environment responds to the conceptus and 3) if we can use these gene or proteins we have identified as interacting between the conceptus and the endometrium to detect successful early pregnancy in a non-invasive sample matrix. More recently my work has identified that key proteins and molecules, packaged in vesicles that can be released from one cell type e.g. the conceptus and alter a different cell type e.g. the endometrium. I have also shown that the way in which these interactions occur may be different when a male conceptus is present compared to a female conceptus. The objectives of the research program are to determine what components of these vesicles are taken up by the endometrium and alter its function. We will also determine how the communication by these vesicles differs between embryos that have different likely hood of pregnancy success (those generated in an animal which are of high quality compared with those generated using assisted reproductive technologies which have less chance of success). We will also examine how male and female conceptuses signal in a different manner to one another. Collectively the results from this work will lead to 1) enhanced understanding of what drives pregnancy success/ embryo loss, 2) novel targets to intervene to prevent embryo loss and 3) markers of successful early pregnancy.

Impact Summary

IMPACT SUMMARY The overall objective of this research is to determine what factors contribute to successful early pregnancy/ embryonic loss in cattle. This is of strategic importance if we are to enhance sustainable livestock production. There are a number of areas what the results arising from this study can have an impact. Short-term Impact: The scientific community and the economy will benefit through the development of highly-skilled researchers, equipped to continue their careers in scientific research in academia or industry. The training of highly skilled PDRFs as well as a technician will enhance the research capabilities within the UK as well as in Brazil. It will also enhance the International reputation of the applicants and their research groups by publishing and disseminating their research in high quality International peer-reviewed journals as well as presenting their work at International conferences. Medium-term Impact: Potential translational impact: Not only will the study enhance our understanding of factors that contribute to pregnancy success/loss in cattle but it has the potential to impact on human health and disease. A number of key findings in the area of reproductive biology have been demonstrated in animal models prior to their investigation in humans. An example of this is the maternal response to embryos with different developmental competencies. Potential impact on policy: The results arising from this proposal will be fed into the United Nations IAEA/FAO joint initiative on establishing an early pregnancy diagnostic for use in the field by farmers in developing countries. The impact of this could be on alterations to policy by advising on when best to diagnose early pregnancy in developing countries for the economic benefit of the farmer. Alternatively results arising from this study could form the basis of an early pregnancy diagnostic, which is a long term impact, requiring involvement of industry, public-private partnerships or non-governmental organisations to develop appropriate devices. Long-term Impact: Economic impact: Although the specific objective of this application is not to generate a commercially viable product or diagnostic for early pregnancy success/ embryo loss the results from this application have the potential to form the basis for one. The identification of specific factors from different types of embryos that are a result of the successful communication between the embryo and the maternal environment will be of significant interest to commercial partners and the Knowledge Exchange Fellow can facilitate the linking of the results from this study with the relevant commercial partners. This project may provide the foundation for further work to investigate the use of the identified biomarkers in a non-invasive diagnostic test. This has the potential (10+ years from end of this project) to impact on both beef and dairy farmers to enhance productivity and economic prosperity.

Committee	Research Committee A (Animal disease, health and welfare)
Research Topics	Animal Health, Animal Welfare
Research Priority	X – Research Priority information not available
Research Initiative	BBSRC-Brazil (FAPESP) joint funding of research [2010-2015]
Funding Scheme	X – not Funded via a specific Funding Scheme

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