Iron is an essential nutrient required by all tissues for cellular and metabolic processes. During pregnancy, iron requirements greatly increase to support placental growth, fetal development, and maternal health. Iron deficiency during pregnancy is associated with poor outcomes for both the mother and fetus, and recognition of the detrimental effects has led to the policy of universal iron supplementation. However, epidemiological studies show a U-shaped association between maternal iron marker ferritin and risk of adverse pregnancy outcomes. Ferritin increases with not only iron loading, but also inflammation. Thus, the association of high ferritin with adverse outcomes may be related to high iron, inflammation, or both. A recent NIH workshop on ?Iron Screening and Supplementation in Iron-replete Pregnant Women and Young Children? identified this as a high priority research area. We developed mouse models to study the interaction between iron and inflammation during pregnancy, and observed that in the presence of iron excess, inflammation in the dam caused embryonic lethality, malformations, and lethal damage to fetal endothelial cells. The striking and novel phenotype raises important questions about indiscriminate iron supplementation in inflamed pregnancies and has substantial biomedical significance and translational potential for improving maternal and neonatal health worldwide. We hypothesize that in response to inflammatory stimuli during pregnancy, the mother and/or the fetus produces TNF?, which acts on iron-rich placental and fetal tissues to trigger endothelial cell apoptosis, resulting in fetal injury or demise. We will identify the mechanisms by evaluating: 1) placental and fetal development and response to inflammation; 2) the role of the TNF? pathway in iron-mediated apoptosis; and 3) the interaction of iron and a broader spectrum of pathogen-derived molecules from viruses and bacteria. The applicant is a graduate student in the top-ranked Ph.D. program in Physiology and is a member of the Center for Iron Disorders, one of the most productive and influential laboratories at UCLA. Her sponsors are the leading experts in iron biology, are dedicated to the translation of basic research, and have an outstanding record of mentorship. The candidate has an excellent academic record and is well prepared for the proposed research and for her future career in academic research. She has proposed a training plan that expands her scientific background in clinical hematology and reproductive sciences, provides relevant didactic training in courses including statistics and ethical research conduct, and expands her repertoire of advanced technical and lab management skills. UCLA is a renowned academic research center with extensive resources, including scientific seminars, an electronic library system, excellent core facilities, and an accomplished network of researchers. In summary, this innovative research proposal has high biomedical significance and translational potential. The proposal together with a personalized and systematic training plan in an outstanding laboratory at a leading research university provides an ideal vehicle for the applicant?s career development.
Our project studies the innovative and translationally relevant interaction of iron and inflammation in pregnancy. We propose to define the mechanism by which iron and inflammation synergize to cause adverse fetal outcomes. That information could provide a gateway to new nutritional recommendations with the long-term goal of improving maternal and neonatal health worldwide.
