A mouse model of placental insufficiency with abnormal renal medullary patterning

胎盘功能不全伴肾髓质模式异常的小鼠模型

• 批准号: 7585522
• 负责人: Mark P. de Caestecker
• 金额: $ 22.99万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7585522
• 关键词: A Mouse; Accounting; Address; Adult; Affect; Apoptosis; Apoptotic; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Characteristics; Child; Chimera organism; Chronic Kidney Failure; Defect; Development; Diabetes Mellitus; Diploidy; Disease; Dysplasia; Embryo; Female; Fetal Growth; Fetal Growth Retardation; Fetus; Foundations; Future; Gene Transfer Techniques; Genetic; Goals; Growth; Growth Factor; Health; Heart; Human; Hyperbaric Oxygenation; Hypertension; Hypoxia; Infant; Inherited; Insulin-Like Growth Factor I; Kidney; Kidney Diseases; Kidney Failure; Knockout Mice; Life; Liver; Mediating; Modeling; Mus; Mutant Strains Mice; Nephrons; Newborn Infant; Nutritional; Organ; Pathway interactions; Patients; Pattern; Perinatal mortality demographics; Phenotype; Placenta; Placental Insufficiency; Play; Pregnancy; Process; Renal function; Role; Signal Transduction; Stress; Study models; TP53 gene; Testing; Tissues; X Chromosome; base; comparative; fetal; genetic analysis; in vivo; kidney medulla; mouse model; mutant; nephrogenesis; prevent; research study; response; tool

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.

描述（由申请人提供）：在美国，妊娠晚期胎盘功能不全是子宫内生长迟缓（IUGR）的最常见原因。这对胎儿生长产生深远影响，增加围产期死亡率，并容易在成年后患上糖尿病、心血管和肾脏疾病。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，对调节 IUGR 的胎儿机制的分析受到阻碍。我们的初步研究表明，具有胎盘功能不全的 Cited1 突变小鼠提供了一种强大的 IUGR 新模型。除了胎儿生长整体下降之外，胎盘 Cited1 的缺失还会促进妊娠晚期肾髓质的异常模式，并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，我们的初步研究并未确定缺氧在促进 Cited1 突变小鼠细胞凋亡和肾模式缺陷中的作用。此外，胎盘中 Cited1 的孤立缺失足以诱发 IUGR 和肾脏模式缺陷的明确证据仍有待确定。因此，本提案的目的是确定缺氧在调节胎盘功能不全的 Cited1 突变小鼠细胞凋亡和肾脏模式中的作用（目标 1），并提供证据证明仅胎盘中 Cited1 表达缺失就足以诱导这些小鼠的 IUGR 和肾脏模式缺陷（目标 2）。这些研究将为使用 Cited1 突变小鼠对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进行明确分析奠定基础。 公共健康相关性：胎盘功能不全是美国宫内（或胎儿）生长迟缓的最常见原因，对胚胎生长具有深远影响，可导致新生儿早期死亡，并在以下疾病的发展中发挥作用： 成人生活中的糖尿病和肾衰竭。由于缺乏这种疾病的小鼠模型，阻碍了对导致这些问题的过程的理解。这些研究将利用一种新的小鼠模型来探讨为什么胎盘功能不全会导致胎儿生长和肾脏发育异常，并为未来的研究奠定基础，有助于防止宫内生长迟缓儿童出现这些问题。