A mouse model of placental insufficiency with abnormal renal medullary patterning

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DESCRIPTION (provided by applicant): Late gestational placental insufficiency is the commonest cause of intrauterine growth retardation (IUGR) in the USA. This has profound effects on fetal growth which increases perinatal mortality and predisposes to the development of diabetes, cardiovascular and renal disease in adult life. Understanding the fetal mechanisms mediating these effects could therefore have a major impact on human health and disease. Analysis of the fetal mechanisms regulating IUGR has been hampered by a lack of reliable mouse models of late gestational placental insufficiency. Our preliminary studies suggest that Cited1 mutant mice with placental insufficiency provide a powerful new model of IUGR. In addition to a global reduction in fetal growth, loss of placental Cited1 promotes abnormal patterning of the renal medulla during late gestation associated with increased renal medullary apoptosis and hypoxia. These findings parallel observations made in other models of IUGR, and provide the opportunity to use mouse genetic tools to explore the fetal mechanisms that cause IUGR and renal patterning defects associated with placental insufficiency. Our preliminary studies do not however, establish the role of hypoxia in promoting apoptosis and renal patterning defects in Cited1 mutant mice. Furthermore, definitive evidence that isolated loss of Cited1 in the placenta is sufficient to induce IUGR and renal patterning defects remains to be established. The purpose of this proposal therefore is to define the role of hypoxia in regulating apoptosis and renal patterning in Cited1 mutant mice with placental insufficiency (Aim 1), and to provide evidence that loss of Cited1 expression in the placenta alone is sufficient to induce IUGR and renal patterning defects in these mice (Aim 2). These studies will provide the foundation for definitive analyses of the mechanisms regulating organ growth and renal patterning defects associated with placental insufficiency using Cited1 mutant mice.PUBLIC HEALTH RELEVANCE: Placental insufficiency is the commonest cause of intrauterine (or fetal) growth retardation in the USA, and has profound effects on growth of the embryo that can cause early death in the newborn and plays a role in the development of diseases such as diabetes and kidney failure in adult life. Understanding the processes that cause these problems are hampered by a lack of mouse models of this disease. These studies will explore why placental insufficiency causes these abnormalities in fetal growth and kidney development using a new mouse model of this disease, and will lay the foundation for future studies that will help to prevent these problems from occurring in children with intrauterine growth retardation.