Genetic Regulation of Surfactant Deficiency

描述（由申请人提供）：性别、遗传连锁、复发性家族病例、鼠系靶向基因消融研究以及新生儿呼吸窘迫综合征风险的种族差异表明新生儿肺表面活性物质缺乏症的遗传调节。成功的胎儿-新生儿肺转变需要肺表面活性物质的产生，这是一种磷脂蛋白膜，在呼气末衬在肺泡上并保持肺泡通畅。我们的目标是了解干扰肺表面活性物质代谢和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种基因对表面活性物质代谢至关重要：表面活性物质蛋白B（SFTPB）、表面活性物质蛋白C（SFTPC）和ATP结合盒转运蛋白ABCA 3（ABCA 3）。为了了解基因调控机制，我们将通过检验SFTPB、SFTPC和ABCA 3基因变异破坏肺表面活性物质代谢的假设，研究这些基因变异与新生儿呼吸窘迫综合征的相关性。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评估表面活性蛋白B和C表达的定量和定性差异，使用稳定同位素标记的前体进行体内代谢标记以估计表面活性蛋白B和C以及磷脂代谢率，以及提供统计功效的队列大小（0.8），我们将使用种族特异性、严重程度分层的病例对照（N=480）和病例比较（N=250）设计来了解基因调控，通过破坏表面活性剂蛋白B或C的表达或改变其加工或通过破坏表面活性剂蛋白B或C的表达或改变表面活性剂蛋白B或C的加工而引起表面活性剂缺乏的代谢机制。在人类新生婴儿中的表面活性剂磷脂组合物。对肺表面活性物质缺乏的遗传调控的进一步了解将提出新的诊断策略来识别和分类高危婴儿，并提出针对肺表面活性物质代谢中的离散步骤的治疗策略来改善新生儿呼吸窘迫综合征婴儿的结局。3种基因（表面活性蛋白B、表面活性蛋白C和ATP结合盒转运蛋白A3）中任何一种的遗传缺陷通过破坏肺表面活性物质的代谢而引起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物质代谢中的离散步骤的破坏联系起来。这些研究将提高诊断能力，并提出新的策略，以纠正新生儿表面活性物质缺乏症。

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.