Work in this theme takes place both in clinical settings and at the basic biological level. The new Centre for Trophoblast Research is promoting research on placental biology.
Clinical research is focused on the analysis of clinical, biochemical and ultrasonic factors predictive of subsequent adverse outcome of pregnancy. Key findings include the relationship between low maternal levels of a placentally derived protein (PAPP-A) in early pregnancy and the later risk of poor fetal growth, pre-eclampsia and stillbirth; and the relationship between maternal serum levels of alpha-fetoprotein in the first half of pregnancy and the risk of the infant subsequently dying from sudden infant death syndrome in the first year of life.
Work in angiogensis and reproduction focuses on the biology of the lining of the womb (the endometrium). This programme of work studies the role of the development of new blood vessels in the physiological control of menstruation and in the development of pathological conditions such as endometriosis. Through this work a new model of endometriosis has been developed, which is being exploited for the assessment of novel medications. The implantation of the developing embryo in the womb and the role of angiogenesis in the formation and development of the placenta are also being studied. This has led to successful collaborations with those having interests in early placentation and the effect of varying levels of oxygen in early pregnancy in determining placental function.
Genomic imprinting is a form of epigenetic gene regulation in mammals which results in the copy of either the mother or the father being turned off. The "imprinted genome" includes less than 1% of the human genes but is essential for normal development and influences key physiological pathways that impact on the health of the mother and the baby. Research aims at unravelling how imprinting works at the various levels, using multi-disciplinary approaches that include genetics, molecular biology, developmental biology, physiology and animal modelling. Researchers want to know how imprinted genes control pre- and post-natal nutritional resources in several organ systems, from the placenta to the brain, and in the context of the developing organism. Other main interests include the study of imprinting defects during pregnancy that impact on the growth trajectory of the baby and the wellbeing of the mother (e.g. intra-uterine growth restriction and overgrowth, maternal metabolism, pre-eclampsia, cancer). Research is also being focused on the dynamics of epigenetic marking systems, how these are influenced by environmental factors, and links with early growth programming, metabolism and disease risk in later life.
Work on fetal growth and metabolism has shed light on the role of the hormonal system producing cortisol (the hypothalamo-pituitary adrenal axis) in both fetal preparation for birth and in the control of the onset of labour. Epidemiological studies around the world have suggested that the environment in the womb may be a critical determinant of cardiovascular and metabolic predisposition towards a range of diseases in later life, in particular those of the cardiovascular system. Biological studies of the mechanisms that link the intra-uterine environment have suggested that the explanation may lie in activation of the HPA axis by acute and chronic physiological stressors, in particular arterial hypoxaemia. Studies have also addressed the association between oxidative stress and cardiovascular and endocrine function in later life.
Research in reproductive immunology includes studies of the mechanisms that allow growth of the antigenically foreign conceptus without stimulating rejection by the mother's immune system: one of the most fascinating questions in immunology. The role of the maternal uterine immune system in regulating the process of placentation is another aspect. How the dominant population of uterine leukocytes, Natural Killer (NK) cells recognise MHC Class I ligands on fetal trophoblast cells and how might this result in altered trophoblast function is a key issue. There is a view of the maternal-fetal relationship that does not consider the placenta as akin to an allograft that must avoid rejection by maternal T cells. Instead several molecular recognition systems have been defined, whereby cells of the innate immune system discern and respond to the placenta.
Cancer of the female reproductive organs is a a significant health problem. Over 80% of patients with ovarian cancer respond to primary chemotherapy treatment. However, the majority of patients develop recurrence within two years of diagnosis and die from chemotherapy-resistant disease. Research is focused on understanding clinically relevant mechanisms of drug resistance by combining translational clinical trials with in-vitro functional studies. Work has identified a novel pathway of clinical paclitaxel resistance in ovarian cancer. Others have designed translational ovarian cancer studies in which gene expression analysis of serial biopsies was used to identify predictive markers of treatment response. There are ongoing studies to advance the understanding of in vivo response to chemotherapy in ovarian cancer or radiotherapy in cervical cancer using dynamic contrast MRI. There are large international collaborations in breast and ovarian cancer to identify novel genetic associations. Work on whole genome association study for breast cancer resulted in the identification of novel susceptibility loci that were independently validated in large case-control studies. The Ovarian Cancer Association Consortium is conducting a genome wide association study in ovarian cancer. The Cambridge Breast Unit has discovered novel genetic prognostic signatures in ER positive breast cancer. CancerGRID is a national project that is aimed at developing software tools to combine clinical and molecular data to facilitate high quality translational studies. There is a national translational trial in breast cancer in which gene e xpression analysis of serial biopsies will be used to indentify novel predictive markers of chemotherapy response.