Genetic Regulation of Surfactant Deficiency

表面活性剂缺乏的基因调控

• 批准号: 7828089
• 负责人: Francis Sessions Cole
• 金额: $ 70.9万
• 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/7828089
• 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）：对性别、遗传连锁、复发性家族病例、小鼠谱系中的靶向基因消融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症的基因调控。成功的胎儿-新生儿肺转变需要产生肺表面活性剂，这是一种磷脂蛋白膜，可排列肺泡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。对人类新生儿的研究表明，3 个基因对于表面活性剂代谢至关重要：表面活性剂蛋白 B (SFTPB)、表面活性剂蛋白 C (SFTPC) 和 ATP 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 的基因变异破坏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联。使用高通量自动测序进行基因分型，使用多维蛋白质鉴定技术来评估表面活性剂蛋白 B 和 C 表达的定量和定性差异，使用稳定同位素标记前体进行体内代谢标记来估计表面活性剂蛋白 B 和 C 和磷脂代谢率，以及提供统计功效 (0.8) 的队列大小，我们将使用种族特异性、 严重程度分层病例对照（N = 480）和病例比较（N = 250）设计旨在了解基因调控的代谢机制，这些机制通过破坏人类新生儿中表面活性剂蛋白B或C的表达或改变加工或破坏表面活性剂磷脂组成而导致表面活性剂缺乏。更好地了解表面活性剂缺乏的遗传调控将提出新的诊断策略来识别和分类高危婴儿，以及针对肺表面活性剂代谢的离散步骤的治疗策略，以改善患有新生儿呼吸窘迫综合征的婴儿的结局。 3 种基因（表面活性剂蛋白 B、表面活性剂蛋白 C 和 ATP 结合盒转运蛋白 A3）中任何一种的遗传缺陷都会通过破坏肺表面活性剂的代谢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的遗传密码的特定变化与人类新生儿肺表面活性剂代谢中离散步骤的破坏联系起来。这些研究将提高诊断能力，并提出纠正新生儿表面活性剂缺乏的新策略。