Growth of the placenta is key to support of the developing fetus, but we still know very little of the processes that regulate its development. We will be studying the molecular mechanisms that control the development of trophoblast lineages in the equine placenta, as well as how these processes are disrupted in a compromised pregnancy. Related to this work, we are also investigating structural genetic variants and SNPs associated with fetal lethality. We have identified microdeletions and microduplications (loss and gain of small segments of chromosomes called copy number variants) that are associated with pregnancy loss. The role of CNVs in normal placental growth, as well as pregnancy failure, is poorly understood. We plan to characterize these CNVs in healthy and failing placentae. We are also interested in identifying variants that influence non-lethal conditions of the fetus such as growth restriction and congenital musculoskeletal disorders.
Our projects investigate the genetic, molecular and cellular mechanisms involved in early development of the placenta and fetus. By identifying the essential genes and proteins key to a successful pregnancy, and understanding their role within the placenta, we can gain valuable insights into mare and human placental biology, potentially leading to new diagnostic markers for placental health. Ultimately, this knowledge may pave the way for innovative interventions that optimize fetal growth and reduce the risk of adult disease susceptibility.
Early pregnancy loss (EPL) in farm animals and horses results in significant economic losses, and when it occurs in women, can also cause great emotional distress. Despite its clear importance to all these mammalian species, treatments that prevent or reduce the risk of early pregnancy loss remain scarce. This is related to an inability to identify the underlying cause of the pregnancy loss as well as a difficulty in obtaining relevant suitable fetal and placental material from healthy and failing pregnancies within the first 6 weeks of conception. Whilst rodent models have been able to go some way to help elucidate specific molecular pathways of early pregnancy, they do not replicate the naturally occurring clinical condition of EPL. We have systems optimized to study both normal pregnancy and failing pregnancies in the mare over this important 6 week period. One of our focuses is to identify genetic causes of early pregnancy loss that can lead to new diagnostic tests and treatments. We have recently identified two phenomena associated with early pregnancy failure in the mare: aneuploidy (loss of gain of a whole chromosome) and copy number variation (CNV) (small segments of chromosomes duplicated or deleted). Current research is focusing on the mechanisms that lead to the development of CNV in the placenta as well as the consequences of both pathogenic CNVs as well as widespread disruption of the genome by CNVs.
We now know that placental growth is intricately linked not only to the successful delivery of a live foal but also importantly in programming a fetus for lifelong health. Further, over the last 10 years, significant leaps forward have been made in other species in the development of novel systems to deliver therapeutics directly to the placenta, and as a consequence treat placental pathologies. Use of these approaches require a complex understanding of how the placenta grows and functions, information we know little about in the mare and for which gaps remain in human placental biology. We are exploring exactly what proteins are essential for placental development of the early placenta and exactly what cells within the placenta that these proteins act upon. In the long term, these key proteins could be monitored in the serum of pregnant mares as a marker of placental health as it is known from other species that the placenta sheds molecules that can be detected in the mother’s blood stream. In the long term, the key proteins identified in the study could also inform the development of new interventional approaches in pregnancy that aim to optimize fetal growth and reduce the chance of programming an individual for susceptibility to adult diseases.
Over the last decade, the concept of Developmental Origins of Health and Disease has gained great traction across all species and the horse is no exception. Nevertheless, we are only just starting to scratch the surface on the important implications of periconceptual and pregnancy exposures for long term health and performance. Congenital developmental orthopaedic disorders (cDOD) are the most significant contributor to Thoroughbred (TB) mortality and the most common reason for a veterinary surgeon to examine a foal in the first week of life (Mouncey et al, 2022). Further, mild to moderate disease that does not resolve can have long term effects on musculoskeletal health and subsequently athletic and/or economic performance. Despite the clear importance of cDOD, little is known about the underlying aetiology.
In this project we are collaborating with epidemiologist Prof. Kristien Verheyen (Royal Veterinary College UK) and clinician Dr Liam MacGillivray (Newmarket Equine Hospital), to investigate the contribution of gestational exposures as well as genetic variants to the development of cDOD in Thoroughbred foals. In line with the laboratories interests in early pregnancy, we are particularly interested in identifying causative genetic variants involving genes responsible for early embryonic patterning in the limb, that when disrupted, may result in severe cases of angular and flexural limb deformities. Our hypothesis is these will mostly originate in early embryonic and fetal development. These findings will inform management and veterinary practices which can be modified to minimize the exposure to risk factors for these conditions, ultimately minimizing the incidence of conformational abnormalities, and by association foaling complications.
Pregnancy loss in the mare can occur anytime between conception and foaling. Currently veterinary surgeons have limited tools available to them to identify non-infectious reasons for a pregnancy to fail. We recently found the most common non-infectious cause of pregnancy loss is aneuploidy, the gain or loss of a whole chromosome that creates a significant genetic imbalance often incompatible with life (Shilton et al, 2020). Small genetic changes such as those involving a single point in the fetuses’ genome can also lead to pregnancy loss, such as fragile foal syndrome recently reported in a Thoroughbred and better known in Warmbloods. We are working with Prof. Madeleine Campbell and Prof Richard Lea, University of Nottingham, with the aim to develop blood and tissue tests with the capacity to concurrently monitor fetal genetic health and identify fetal sex in the pregnant mare. Testing could be applied retrospectively to diagnose the underlying cause of pregnancy loss using tissue as well as identify pregnant mares at future risk of losing their pregnancy.
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