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生长迟缓（IUGR）最常见的原因。这对胎儿生长产生了深远的影响，增加了围产期死亡率，并在成年后易患糖尿病、心血管疾病和肾脏疾病。因此，了解介导这些影响的胎儿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小鼠模型，胎儿调节IUGR机制的分析一直受到阻碍。我们的初步研究表明，胎盘功能不全的Cited1突变小鼠提供了一种强有力的IUGR新模型。除了全面降低胎儿生长外，胎盘Cited1的缺失还会促进妊娠后期肾髓质的异常模式，与肾髓细胞凋亡和缺氧增加有关。这些发现与其他IUGR模型的观察结果相似，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脏模式缺陷的胎儿机制的机会。然而，我们的初步研究并没有确定缺氧在促进Cited1突变小鼠细胞凋亡和肾脏模式缺陷中的作用。此外，明确的证据表明，胎盘中孤立的Cited1缺失足以诱导IUGR和肾脏模式缺陷，仍有待建立。因此，本研究的目的是确定缺氧在胎盘功能不全的Cited1突变小鼠中调节细胞凋亡和肾脏模式的作用（目的1），并提供证据证明胎盘中Cited1表达缺失足以诱导这些小鼠IUGR和肾脏模式缺陷（目的2）。这些研究将为明确分析Cited1突变小鼠与胎盘功能不全相关的器官生长和肾脏模式缺陷的调节机制提供基础。公共卫生相关性：在美国，胎盘功能不全是宫内（或胎儿）生长迟缓的最常见原因，对胚胎生长有深远影响，可导致新生儿早期死亡，并在成人生活中糖尿病和肾衰竭等疾病的发展中发挥作用。由于缺乏这种疾病的小鼠模型，对导致这些问题的过程的理解受到了阻碍。这些研究将探索胎盘功能不全导致胎儿生长和肾脏发育异常的原因，并将为未来的研究奠定基础，有助于预防这些问题在宫内发育迟缓儿童中发生。

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.