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妊娠期肝内胆汁淤积（ICP）的发生率为1.5-4%，并且与血清胆汁酸浓度有关。虽然母亲的健康问题可以得到解决，但胎儿和产后并发症常常会给婴儿带来不良后果，包括与呼吸窘迫相关的死亡。我们对导致 ICP 的遗传因素的了解存在重大差距。我们对缺乏肝胆汁盐输出蛋白（Abcb11 又名 Bsep，ATP 结合盒超家族成员）的小鼠进行的初步研究表明，这种敲除小鼠出现了进行性胆汁淤积，从而首次重现了 ABCB11 缺陷人类的表型。更重要的是，缺乏Abcb11的母鼠在怀孕期间胆汁酸浓度很高，100%的新生小鼠在产后24小时内因呼吸窘迫而死亡。我们对这些探索性研究的主要假设是，母体胆汁酸升高会破坏胎儿肺部的正常发育和成熟。这些探索性研究揭示了一种遗传机制，表明母体 Abcb11 不足是继发于胆汁淤积的新生儿呼吸窘迫的一个潜在危险因素。我们的 R21 目标是阐明 Abcb11 缺陷母亲的胆汁淤积如何导致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具体目标：具体目标 1：我们将检验 Abcb11 缺失母亲的后代肺成熟受损的假设。我们的初步数据使用母体胆汁淤积的体内遗传模型。具体目标 2：我们将检验以下假设：母亲缺乏 Abcb11 会使发育中的胎儿暴露在改变对肺部发育重要的基因表达的环境中。我们的初步数据表明，Abcb11 缺陷母亲的新生儿肺部表面活性剂 B 的表达减少。我们将从机制上确定 Abcb11 缺陷母亲所生的新生儿的肺成熟和功能如何受损。成功完成这些探索性研究将增加我们对母体胆汁淤积如何破坏产前肺部发育的了解，并有助于为 R01 做好准备。我们从这些研究中获得的知识的最终扩展有可能减少呼吸窘迫的不良后果以及产前暴露于母体胆汁淤积后发育中的后代的呼吸损伤程度。