Genetic Regulation of Surfactant Deficiency

表面活性剂缺乏的基因调控

• 批准号: 7588777
• 负责人: Francis Sessions Cole
• 金额: $ 70.78万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-08 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7588777
• 关键词: ABCA3 gene; ATP-Binding Cassette Transporters; Ablation; Alleles; Alveolar; Alveolus; Arts; Biochemical; Diagnostic; Exons; Film; Gender; Gene Targeting; Genes; Genetic; Genetic Code; Genotype; Goals; Haplotypes; Human; Infant; Inherited; Label; Lead; Link; Lung; Mass Fragmentography; Metabolic; Metabolism; Methods; Mus; Neonatal; Newborn Infant; Newborn Respiratory Distress Syndrome; Pathway interactions; Phospholipids; Process; Production; Proteins; Pulmonary Surfactant-Associated Protein B; Pulmonary Surfactant-Associated Protein C; Pulmonary Surfactants; Race; Recurrence; Regulation; Risk; Severities; Severity of illness; Technology; Testing; Therapeutic; Variant; case control; cohort; design; expiration; fetal; genetic linkage; genetic variant; high risk; high risk infant; improved; in vivo; infant outcome; novel diagnostics; novel strategies; respiratory distress syndrome; surfactant; surfactant deficiency; surfactant deficiency in infants

DESCRIPTION (provided by applicant): Genetic regulation of neonatal pulmonary surfactant deficiency has been suggested by studies of gender, genetic linkage, recurrent familial cases, targeted gene ablation in murine lineages, and by racial disparity in risk of neonatal respiratory distress syndrome. Successful fetal-neonatal pulmonary transition requires production of the pulmonary surfactant, a phospholipid-protein film that lines alveoli and maintains alveolar patency at end expiration. Our goal is to understand the genetic mechanisms that disrupt pulmonary surfactant metabolism and cause neonatal respiratory distress syndrome. Studies in human newborn infants have demonstrated that 3 genes are critical for surfactant metabolism: surfactant protein B (SFTPB), surfactant protein C (SFTPC), and an ATP-binding cassette transporter, ABCA3 (ABCA3). To understand genetic regulatory mechanisms, we will investigate the association of variation in each of these genes with neonatal respiratory distress syndrome by testing the hypothesis that genetic variants in SFTPB, SFTPC, and ABCA3 disrupt pulmonary surfactant metabolism. Using high throughput automated sequencing to genotype, multidimensional protein identification technology to assess quantitative and qualitative differences in surfactant protein B and C expression, in vivo metabolic labeling with stable isotopically labeled precursors to estimate surfactant protein B and C and phospholipid metabolic rates, and cohort sizes that provide statistical power (0.8), we will use race-specific, severity-stratified case-control (N=480) and case comparison (N=250) designs to understand genetically regulated, metabolic mechanisms that cause surfactant deficiency by disrupting expression or altering processing of surfactant proteins B or C or by disrupting surfactant phospholipid composition in human newborn infants. Improved understanding of genetic regulation of surfactant deficiency will suggest novel diagnostic strategies to identify and categorize high risk infants and therapeutic strategies that target discrete steps in pulmonary surfactant metabolism to improve outcomes of infants with neonatal respiratory distress syndrome. Inherited deficiencies in any one of 3 genes (surfactant protein B, surfactant protein C, and ATP-binding cassette transporter A3) cause neonatal respiratory distress syndrome by disrupting metabolism of the pulmonary surfactant. We will use state of the art methods to link specific changes in the genetic code of each of these genes with disruption of discrete steps in the metabolism of the pulmonary surfactant in human newborn infants. These studies will lead to improved diagnostic capabilities and suggest novel strategies to correct surfactant deficiency in newborn infants.

描述(由申请人提供)：性别、遗传连锁、反复家族性病例、小鼠谱系中的靶向基因去除以及新生儿呼吸窘迫综合征风险的种族差异的研究表明，新生儿肺表面活性物质缺乏的遗传调节。成功的胎儿-新生儿肺过渡需要产生肺表面活性物质，这是一种磷脂-蛋白质膜，使肺泡排列，并在呼气末保持肺泡通畅。我们的目标是了解扰乱肺表面活性物质代谢并导致新生儿呼吸窘迫综合征的遗传机制。对新生儿的研究表明，有3个基因对表面活性物质代谢起关键作用：表面活性蛋白B(SFTPB)、表面活性蛋白C(SFTPC)和三磷酸腺苷结合盒转运蛋白ABCA3(ABCA3)。为了了解基因调控机制，我们将通过检验SFTPB、SFTPC和ABCA3基因变异扰乱肺表面活性物质代谢的假设，来研究这些基因的变异与新生儿呼吸窘迫综合征的关系。我们将使用高通量自动测序技术进行基因分型，使用多维蛋白质鉴定技术来评估表面活性蛋白B和C表达的数量和质量差异，使用稳定的同位素标记前体进行体内代谢标记来估计表面活性蛋白B和C以及磷脂代谢率，并使用提供统计能力的队列大小(0.8)，我们将使用种族特定的、严重程度分层的病例对照(N=480)和病例比较(N=250)设计，以了解通过干扰表面活性蛋白B或C的表达或改变其加工，或通过扰乱表面活性物质磷脂成分而导致表面活性物质缺乏的基因调控代谢机制。对肺表面活性物质缺乏的遗传调控的更深入的了解将提出新的诊断策略来识别和分类高危婴儿，以及以肺表面活性物质代谢的离散步骤为目标的治疗策略以改善新生儿呼吸窘迫综合征的预后。3个基因(表面活性蛋白B、表面活性蛋白C和三磷酸腺苷结合盒转运体A3)中任何一个的遗传缺陷会破坏肺表面活性物质的新陈代谢，从而导致新生儿呼吸窘迫综合征。我们将使用最先进的方法将这些基因中每一个的遗传密码的特定变化与人类新生儿肺表面活性物质代谢的离散步骤的中断联系起来。这些研究将提高诊断能力，并提出纠正新生儿表面活性物质缺乏的新策略。