A genetic model of cholestasis induced neonatal

新生儿胆汁淤积的遗传模型

基本信息

批准号：
8442892
负责人：
JOHN D SCHUETZ
金额：
$ 22.13万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8442892
关键词：
Affect Bile Acids Binding Biological Models Cells Cholestasis Complex Coupled Data Defect Development Differentiation Antigens Environment Epidemiology Experimental Designs Exposure to Family Fetal Lung Fetus Foundations Frequencies Future Gene Expression Genes Genetic Genetic Models Genetic screening method Genotype Goals Health Hepatic Human Immunoblotting Immunohistochemistry Incidence Infant Infant Health Irrigation Knockout Mice Knowledge Lead Link Lung Monitor Mothers Mus Neonatal Pathogenesis Pattern Pharmaceutical Preparations Phase Phenotype Pregnancy Preparation Production Protein Export Pathway Respiratory distress Respiratory physiology Risk Factors Secondary to Serum Staging Sudden infant death syndrome Testing Time Undifferentiated alveolar epithelium base bile salts design fetal in vivo insight intrahepatic cholestasis of pregnancy lung development lung maturation maternal serum member mortality neonate novel therapeutic intervention offspring pneumocyte postnatal pregnant prenatal prenatal exposure public health relevance research study respiratory respiratory distress syndrome surfactant time use

项目摘要

DESCRIPTION (provided by applicant): Recent epidemiological data indicate intrahepatic cholestasis of pregnancy (ICP) has an incidence of between 1.5-4% and is related to serum bile acid concentrations. While the health problem for the mother can be resolved, fetal and post-natal complications frequently lead to untoward consequences to the infant including mortality related to respiratory distress. There are significant gaps in our knowledge of the genetic factors that cause ICP. Our preliminary studies with a mouse lacking the hepatic bile salt export protein (Abcb11 aka Bsep, a member of the ATP binding cassette superfamily) indicated that this mouse knockout developed progressive cholestasis thereby recapitulating, for the first time the phenotype of humans with ABCB11 deficiency. More importantly, dams lacking Abcb11 have high concentrations of bile acids during pregnancy and 100% of the neonatal mice die within 24h of postnatal respiratory distress. Our main hypothesis for these exploratory studies is that elevated maternal bile acids disrupt normal development and maturation of fetal lungs. These exploratory studies reveal a genetic mechanism showing maternal insufficiency in Abcb11 as a potent risk factor for neonatal respiratory distress secondary to cholestasis. Our goal for this R21 is to elucidate how the cholestasis in Abcb11 deficient mothers produces lethal neonatal respiratory distress. To accomplish this we propose two hypothesis driven Specific Aims: Specific Aim 1: We will test the hypothesis that offspring of Abcb11-null mothers have impaired lung maturation. Our preliminary data use an in vivo genetic model of maternal cholestasis. Specific Aim 2: We will test the hypothesis that maternal absence of Abcb11 exposes the developing fetus to an environment that alters expression of genes important for lung development. Our preliminary data indicate that the expression of surfactant B is reduced in the lungs of neonates from Abcb11- deficient mothers. We will determine mechanistically how lung maturation and function is impaired in neonates borne to Abcb11 deficient mothers. Successful completion of these exploratory studies will increase our knowledge of how maternal cholestasis disrupts prenatal lung development and facilitate preparation for an R01. The ultimate extension of the knowledge we acquire from these studies has the potential to reduce the untoward consequences of respiratory distress and the extent of respiratory damage in developing offspring after prenatal exposure to maternal cholestasis.

描述（由申请人提供）：最近的流行病学数据表明，肝内妊娠（ICP）的发生率为1.5-4％，与血清胆汁酸浓度有关。尽管可以解决母亲的健康问题，但胎儿和产后并发症经常会导致对婴儿的不利后果，包括与呼吸窘迫有关的死亡率。我们对引起ICP的遗传因素的了解存在很大的差距。我们使用小鼠缺乏肝胆汁盐输出蛋白的初步研究（ABCB11又名BSEP，ATP结合盒的成员超级家族）表明，该小鼠敲除促进性胆汁淤积，从而缩减了促进性，从而首次进行了ABCB11防御能力的人的表型。更重要的是，缺乏ABCB11的大坝在怀孕期间具有高浓度的胆汁酸，而100％的新生小鼠在产后呼吸窘迫的24小时内死亡。我们对这些探索性研究的主要假设是，升高的母体胆汁酸破坏了胎儿肺的正常发育和成熟。这些探索性研究揭示了一种遗传机制，表明ABCB11的孕产妇不足是胆汁淤积继发的新生儿呼吸窘迫的有效危险因素。我们的R21目标是阐明ABCB11缺乏母亲的胆汁淤积如何产生致命的新生儿呼吸窘迫。为了实现这一目标，我们提出了两个假设驱动的特定目的：特定目的1：我们将检验以下假设：ABCB11-NULL母亲的后代损害了肺部成熟。我们的初步数据使用母体胆汁淤积的体内遗传模型。具体目的2：我们将检验以下假设：孕产妇的缺乏使发展中国家的胎儿暴露于改变基因表达对肺发育重要的环境。我们的初步数据表明，来自ABCB11不足母亲的新生儿肺中表面活性剂B的表达降低。我们将从机械上确定肺部成熟和功能如何受到ABCB11缺乏母亲的新生儿的损害。这些探索性研究的成功完成将提高我们对孕产妇胆汁淤积如何破坏产前肺发育并促进R01的准备的知识。我们从这些研究中获取的知识的最终扩展有可能减少呼吸窘迫的不良后果以及在产前暴露于孕产妇胆汁淤积后发展后代的呼吸损伤程度。