Mother's diet during pregnancy plays an essential role in early foetal development. There is no satisfactory epidemiological evidence to date investigating the relationship between maternal iron during pregnancy, and cardiovascular outcomes in the adult offspring. This project aims to assess the effect of both maternal iron status, measured by serum transferrin receptor to serum ferritin ratio, and iron intake during pregnancy, from diet and supplements, on offspring outcomes. These include blood pressure and weight in the adult offspring, and infant outcomes including birthweight. There is substantial evidence of increased cardiovascular risk with low birthweight. Therefore, the relationship between maternal iron and cardiovascular risk in the offspring will be tested to assess if it is direct or mediated by birthweight. This will be achieved using both prospective and historical cohort designs. Data from three prospective birth cohorts will be used to examine the effect of mat ernal iron intake and status on infant outcomes. Using historical cohort design, the offspring of women with a C282Y mutation, who have higher iron stores than the general population, will be recruited. Their blood pressure, body mass index and waist circumference will be measured and compared to the offspring of women with a wild type gene.

Natural killer (NK) cells eliminate aberrant cells, including pathogen infected and tumourigenic cells. The recognition of an aberrant cell triggers secretory lysosome exocytosis by a NK cell, resulting in the secretion of cytotoxic molecules that kill the target cell. Despite its central role in NK cell cytotoxicity, little is known about the mechanism of secretory lysosome exocytosis. The analysis of immunodeficiency disorders has, however, provided insights into this process. One such disord er familial haemophagocytic lymphohistiocytosis type 4 (FHL-4), is caused by mutations in syntaxin 11, and is characterised by defective NK cell secretory lysosome exocytosis and cytotoxicity. The function of syntaxin 11 is poorly understood, although it is predicted to be a member of the SNARE, a family of proteins that catalyse membrane fusion reactions. This project will test and develop the hypothesis that syntaxin 11 is part of a SNARE complex that catalyses a membrane fusion reaction requi red for secretory lysosome exocytosis by NK cells. These studies will provide new insights into the molecular basis for secretory lysosome exocytosis by NK cells. Furthermore, by determining why syntaxin 11 mutations impair NK cell cytotoxicity, this project will provide information that may ultimately be used to develop therapies for FHL-4.