Molecular Genetics of Congenital Diaphragmatic Hernia

先天性膈疝的分子遗传学

基本信息

批准号：
7278624
负责人：
Daryl Armstrong Scott
金额：
$ 12.98万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-05 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7278624
关键词：
Abdominal Cavity Ablation Affect Animal Model Apoptosis Candidate Disease Gene Caring Cell Proliferation Child health care Chromosome Positioning Chromosome abnormality Chromosomes Clinical Congenital diaphragmatic hernia Cytogenetics DNA Data Defect Development Developmental Biology Diaphragmatic Hernia Embryo Event G-Banding Genes Genetic Genetic Predisposition to Disease Genome Genotype Goals Health Sciences Hereditary Disease Human Human Genetics Individual Infant Invaded Lead Literature Localized Location Lung Maps Medical Medicine Methods Mind Modeling Molecular Molecular Genetics Morbidity - disease rate Mus Mutation Newborn Infant Numbers Outcome Pathway interactions Patients Pattern Phenotype Physicians Process Pulmonary Hypertension Race Range Rattus Reporting Research Personnel Research Proposals Resolution Respiratory Diaphragm Role Sampling Scientist Screening procedure Signal Pathway Standards of Weights and Measures Structure Technology Test Result Texas Therapeutic Time Tissue Sample Tissues Training Transcription factor genes Tretinoin Universities WT1 gene apoAI regulatory protein-1 base college comparative genomic hybridization genome-wide analysis human study insight mortality mouse model nerve supply new technology novel programs repository sex spatiotemporal transcription factor

项目摘要

DESCRIPTION (provided by applicant): The applkicant is a senior clinical genetics fellow who has completed his clinical training. His long-term objective is to become an independent physician scientist focused on studying genetic disorders that impact the health of children. This application will provide the candidate with training in developmental biology, new technologies in human genetics, and mouse genetics. The overall scientific goal is to identify and characterize genes responsible for congenital diaphragmatic hernia (CDH). CDH is a developmental abnormality in which regions of the diaphragm fail to form, allowing the contents of the abdominal cavity to invade the space normally reserved for the developing lung. CDH affects approximately 1 in 2,500 newborns. Mortality ranges from 30 to 60%, and infants who survive often have significant morbidity from pulmonary hypoplasia and pulmonary hypertension. Specific aims for this study include: 1) establishing a collaborative DNA repository for the study of CDH, 2) screening candidate genes for CDH-causing mutations, 3) identifying and mapping chromosomal regions involved in CDH using novel comparative genomic hybridization (CGH) technology, and 4) characterizing a mouse model of CDH. Candidate genes, selected based on chromosome position and putative function, will be screened for CDH-causing mutation by direct sequencing. DNA from individuals with CHD will be screened for abnormalities by G-banded chromosome analysis and CGH using a genome-wide microarray of over 20,000 overlapping clones with a approximately 300 kb resolution. A CDH mouse model that mimics the most common form of CDH in human has been developed by selective ablation of COUP-TFII, a gene for transcription factor regulated by the retinoic acid pathway. The candidate will characterize these mice by determining the effect of COUP-TFII ablation on diaphragm musculature, innervation, cellular proliferation, as well as apoptosis. Identifying and characterizing the genes that cause CDH may lead to the development of new preventative and therapeutic strategies, and will provide insight into the molecular basis of diaphragm development.

描述（由申请人提供）：申请人是一位已完成临床培训的高级临床遗传学研究员。他的长期目标是成为一名独立的医师科学家，专注于研究影响儿童健康的遗传性疾病。该应用程序将为候选人提供发育生物学、人类遗传学新技术和小鼠遗传学方面的培训。总体科学目标是识别和表征导致先天性膈疝 (CDH) 的基因。 CDH 是一种发育异常，膈肌区域无法形成，导致腹腔内容物侵入通常为发育中的肺部保留的空间。 CDH 影响大约 2,500 名新生儿中的 1 人。死亡率为 30% 至 60%，幸存的婴儿通常因肺发育不全和肺动脉高压而发病。本研究的具体目标包括：1) 建立用于 CDH 研究的协作 DNA 存储库，2) 筛选引起 CDH 的突变的候选基因，3) 使用新型比较基因组杂交 (CGH) 技术识别和绘制 CDH 涉及的染色体区域和 4) 描述 CDH 小鼠模型的特征。根据染色体位置和假定功能选择的候选基因将通过直接测序来筛选引起 CDH 的突变。将使用由 20,000 多个重叠克隆组成的全基因组微阵列（分辨率约为 300 kb），通过 G 带染色体分析和 CGH 筛查先心病患者的 DNA 是否存在异常。通过选择性消融 COUP-TFII（一种受视黄酸途径调节的转录因子基因），开发了模拟人类最常见 CDH 形式的 CDH 小鼠模型。候选人将通过确定 COUP-TFII 消融对膈肌组织、神经支配、细胞增殖以及细胞凋亡的影响来表征这些小鼠。识别和表征导致 CDH 的基因可能会导致新的预防和治疗策略的开发，并将提供对膈肌发育的分子基础的深入了解。