In vitro Expression of Hormone Regulated Genes: COUP-TFII in CDH

激素调节基因的体外表达：CDH 中的 COUP-TFII

基本信息

批准号：
7935118
负责人：
Ming-Jer Tsai
金额：
$ 8.91万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2010-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7935118
关键词：
15q Abdomen Ablation Accounting Acids Address Affect Animal Model Anterior Candidate Disease Gene Childhood Chromosome Deletion Chromosome abnormality Chromosomes Clinical Congenital Abnormality Congenital diaphragmatic hernia Cytogenetic Analysis Defect Development Diagnostic Diaphragmatic Hernia Disease Embryo Embryonic Development Etiology Exhibits Failure Fishes Genes Genotype Growth and Development function Hepatic Hormones Human In Vitro Individual Intervention Intestines Knock-out Knockout Mice Life Live Birth Liver Lung Maps Mesenchymal Mesenchyme Mesentery Morphogenesis Mus Mutation Newborn Infant Nuclear Orphan Receptor Nuclear Receptors Organ Patients Pattern Phenotype Play Primitive foregut structure Pulmonary Hypertension Radial Research Personnel Respiratory Diaphragm Retinoids Role Screening procedure Secondary to Signal Transduction Spleen Stomach Thoracic cavity structure Tissues Tretinoin WT1 gene angiogenesis apoAI regulatory protein-1 cardiogenesis genetic analysis improved insight lung development malformation member mortality mouse Cre recombinase mouse development mutant neonatal death nitrofen programs recombinase

项目摘要

DESCRIPTION (provided by applicant): Congenital diaphragmatic hernia (CDH), a life-threatening birth defect, is a major cause of pediatric mortality and mobility. The pathological anomalies are characterized by the inappropriate protrusion of the abdominal contents, possibly including the stomach, liver, intestines and spleen, through an improperly formed diaphragm into the thoracic cavity which impairs lung growth and development. In addition to the secondary defect resulting from protrusion of abdominal contents, lung development itself may be also effected and contribute to CDH phenotypes in these patients. Although the disease was described more than 350 years ago, the etiology of CDH is poorly understood. Using a conditional null mutant in which COUP-TFII is deleted in the mesentery, we showed that tissue specific null mutants of COUP-TFII exhibit Bochdalek CDH, the most common form of CDH. COUP-TFII, a member of orphan nuclear receptors, is expressed in regions critical for the formation of the diaphragm and lung during embryonic development. Ablation of COUP-TFII in the foregut mesenchyme, including the post-hepatic mesenchymal plate (PHMP), results in the malformation of the diaphragm and the failure of appropriate attachment of the PHMP to the body wall. Recently a critical region within 15q26.1-26.2 has been mapped by array CGH and Fish analysis to be deleted in CDH patients. COUP-TFII is one of the four known genes resided within this critical region. Together with results of our COUP-TFII conditional mutants, the genetic analysis implicates COUP-TFII as most likely candidate gene for the most common type of Bochdalek CDH. To delineate how COUP-TFII regulates diaphragm and lung development and how perturbation of proper diaphragm formation might result in CDH, three specific aims are proposed: 1). Analysis of the defects exhibited by the conditional null mice during diaphragm development; 2). Analyze the role of COUP-TFII in lung development and its relationship to CDH; 3). Screen and characterize COUP-TFII mutations in CDH patients. With the proposed study, we hope to provide important insights on morphogenesis of the diaphragm and lung and how malformation of these organs leads to such devastating congenital defects. And eventually, by screening CDH patients for the mutations in COUP-TFII, it will certainly improve the translational prospect in setting up a diagnostic kit and devise an intervention for some CDH patients.

描述（由申请人提供）：先天性膈疝 (CDH) 是一种危及生命的出生缺陷，是儿科死亡和行动不便的主要原因。病理异常的特征是腹部内容物（可能包括胃、肝脏、肠和脾）通过不正确形成的隔膜不适当地突出到胸腔，从而损害肺部生长和发育。除了腹部内容物突出导致的继发性缺陷外，肺部发育本身也可能受到影响并导致这些患者出现 CDH 表型。尽管这种疾病早在 350 多年前就已被描述，但 CDH 的病因却知之甚少。使用肠系膜中 COUP-TFII 缺失的条件无效突变体，我们发现 COUP-TFII 的组织特异性无效突变体表现出 Bochdalek CDH（CDH 的最常见形式）。 COUP-TFII 是孤儿核受体的成员，在胚胎发育过程中对膈肌和肺的形成至关重要的区域表达。前肠间充质（包括肝后间充质板 (PHMP)）中 COUP-TFII 的消融会导致膈肌畸形以及 PHMP 无法正确附着到体壁。最近，通过阵列 CGH 和 Fish 分析绘制了 15q26.1-26.2 内的一个关键区域，并将在 CDH 患者中删除。 COUP-TFII 是位于该关键区域的四个已知基因之一。结合我们的 COUP-TFII 条件突变体的结果，遗传分析表明 COUP-TFII 是最常见的 Bochdalek CDH 类型最有可能的候选基因。为了描述 COUP-TFII 如何调节膈肌和肺部发育以及扰动适当的膈肌形成如何可能导致 CDH，提出了三个具体目标：1)。条件无效小鼠膈肌发育过程中表现出的缺陷分析2）。分析COUP-TFII在肺发育中的作用及其与CDH的关系； 3）。筛查和表征 CDH 患者的 COUP-TFII 突变。通过拟议的研究，我们希望为隔膜和肺的形态发生以及这些器官的畸形如何导致这种毁灭性的先天缺陷提供重要的见解。最终，通过筛查 CDH 患者的 COUP-TFII 突变，肯定会改善建立诊断试剂盒的转化前景，并为一些 CDH 患者设计干预措施。