A mouse model of placental insufficiency with abnormal renal medullary patterning

描述（由申请人提供）：妊娠晚期胎盘功能不全是美国宫内发育迟缓（IUGR）的最常见原因。这对胎儿生长有深远的影响，增加围产期死亡率，并在成年后易患糖尿病、心血管和肾脏疾病。因此，了解胎儿介导这些效应的机制可能对人类健康和疾病产生重大影响。由于缺乏可靠的妊娠晚期胎盘功能不全的小鼠模型，胎儿调节IUGR机制的分析受到阻碍。我们的初步研究表明，Cited1突变小鼠与胎盘功能不全提供了一个强大的新的模型IUGR。除了胎儿生长的总体减少外，胎盘Cited 1的丧失还促进妊娠晚期肾髓质的异常模式，与肾髓质细胞凋亡和缺氧增加相关。这些发现与其他IUGR模型中的观察结果平行，并提供了使用小鼠遗传工具探索导致IUGR和与胎盘功能不全相关的肾模式缺陷的胎儿机制的机会。然而，我们的初步研究并没有建立缺氧在促进Cited1突变小鼠的细胞凋亡和肾模式缺陷中的作用。此外，明确的证据表明，孤立的损失Cited1在胎盘中是足以诱导IUGR和肾脏图案的缺陷仍然有待建立。因此，本提案的目的是确定缺氧在调节胎盘功能不全的Cited1突变小鼠中的细胞凋亡和肾模式中的作用（目的1），并提供证据证明仅胎盘中Cited1表达的丧失就足以诱导这些小鼠中的IUGR和肾模式缺陷（目的2）。这些研究将为使用Cited1突变小鼠确定性分析与胎盘功能不全相关的器官生长和肾模式缺陷的调节机制提供基础。胎盘功能不全是子宫内膜异位症最常见的原因。（或胎儿）生长迟缓在美国，并对胚胎的生长有深远的影响，这可能导致新生儿的过早死亡，并在成年后的糖尿病和肾衰竭等疾病的发展中起作用。由于缺乏这种疾病的小鼠模型，理解导致这些问题的过程受到阻碍。这些研究将探索为什么胎盘功能不全会导致胎儿生长和肾脏发育异常，使用这种疾病的新小鼠模型，并将为未来的研究奠定基础，这将有助于防止这些问题发生在宫内发育迟缓的儿童中。

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.