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SURFACTANT PATHWAY GENE VARIANTS AMONG INFANTS WITH RESPIRATORY DISTRESS SYNDROME

呼吸窘迫综合征婴儿的表面活性剂途径基因变异

基本信息

批准号：
8500434
负责人：
Jennifer Wambach
金额：
$ 12.55万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8500434
关键词：
1 year old ATP-Binding Cassette Transporters Accounting Adult Affect African Age-Years Algorithms Alveolar Biological Biological Assay Candidate Disease Gene Cause of Death Cells Child Clinical Complex Complex Mixtures Computational algorithm Computer software Control Groups Counseling DNA DNA Resequencing Development Diagnostic Discipline of obstetrics Disease Ethnic Origin Ethnic group European Frequencies Gender Genes Genetic Genetic Variation Goals Health Healthcare Heritability Heterogeneity In Vitro Infant Informed Consent Laboratories Linkage Disequilibrium Linkage Disequilibrium Mapping Logic Mentors Metabolism Methods Missouri Modeling Morbidity - disease rate Mutation Newborn Infant Newborn Respiratory Distress Syndrome Outcome Pathway interactions Phenotype Phospholipids Production Proteins Pulmonary Surfactant-Associated Protein B Pulmonary Surfactant-Associated Protein C Pulmonary Surfactants Regression Analysis Reporting Research Research Personnel Resolution Risk Sampling Surface Tension System Technology Testing Therapeutic Time Management Training Translating Twin Studies United States Variant Work alveolar type II cell base career case control clinical care cohort cost experience expiration fitness genetic epidemiology genetic variant genome wide association study improved mortality next generation sequencing novel novel diagnostics novel therapeutics population based reproductive respiratory respiratory distress syndrome skills surfactant tool

项目摘要

DESCRIPTION (provided by applicant): Neonatal respiratory distress syndrome (RDS) is the most common respiratory cause of mortality and morbidity among infants in the United States. While RDS is most commonly attributed to a developmental immaturity of pulmonary surfactant production, a genetic mechanism is suggested by studies of twins, ethnicity, gender, and lethal mutations in surfactant-related genes (SFTPB, SFTPC, and ABCA3). Prior research to define the genetic mechanisms underlying neonatal RDS has focused on common genetic variants within single candidate genes and explains only a small proportion of disease heritability. Research in complex adult diseases that reduce reproductive fitness suggests that combinations of rare, highly penetrant variants in multiple genes account for disease heritability. Our laboratory has identified statistical and functional associations of rare variants in surfactant-related genes with neonatal RDS. The goals of this proposal are to identify gene loci with excess, rare, functional variants that statistically account for the missing heritability of RDS and to develop methods to test the biologic mechanisms by which genetic variants disrupt surfactant metabolism. First, we will use next generation sequencing to determine the population-based frequencies of rare genetic variants among five surfactant-related genes (SFTPC, ABCA3, LPCAT, CHPT, and PCYT1B) using 1,116 infant samples obtained from the Missouri Department of Health. Second, we will determine whether excess, rare, functionally disruptive variants in these five genes are overrepresented among infants with RDS compared to infants without RDS in already available DNA samples with informed consent (N=940 infants of African and European descent). Third, we will use cell-based functional assays to investigate the underlying biologic mechanisms of these disruptive variants. This comprehensive research strategy is novel because we will study candidate genes with higher resolution, use software based algorithms to assess variant functionality, use traditional (regression) and novel (Collapsing Methods, BimBam, logic regression) statistical approaches to evaluate variant interactions, and use cell-based assays to study the functionality of identified variants and combinations of variants. The development of cell-based assays will permit mechanistic study of variants identified through statistical associations and provide the basis for the long-term development of diagnostic and therapeutic approaches for affected infants. The combination of my clinical experience, prior didactic and mentored training in genetic epidemiology, and an integrated training plan that allows me to develop skills in the use of surrogate cell systems will enable me to develop into an independent investigator that can bridge statistical observation with functional mechanism and translate these findings into specific therapeutic approaches for infants with RDS.

描述（由申请人提供）：新生儿呼吸窘迫综合征（RDS）是美国婴儿死亡和发病的最常见呼吸道原因。虽然RDS最常归因于肺表面活性物质产生的发育不成熟，但对双胞胎、种族、性别和表面活性物质相关基因（SFTPB、SFTPC和ABCA 3）的致死突变的研究表明，这是一种遗传机制。先前的研究，以确定新生儿RDS的遗传机制，主要集中在共同的遗传变异的单一候选基因，并解释只有一小部分的疾病遗传性。对降低生殖适应性的复杂成人疾病的研究表明，多个基因中罕见的高度外显变异的组合可以解释疾病的遗传性。我们的实验室已经确定了新生儿RDS的表面活性剂相关基因的罕见变异的统计学和功能关联。该提案的目标是确定具有过量的、罕见的、功能性变异的基因位点，这些基因位点在统计学上解释了RDS的遗传性缺失，并开发方法来测试遗传变异破坏表面活性剂代谢的生物学机制。首先，我们将使用从密苏里州卫生部获得的1,116个婴儿样本，使用下一代测序来确定5个表面活性剂相关基因（SFTPC、ABCA 3、LPCAT、CHPT和PCYT 1B）中罕见遗传变异的人群频率。第二，我们将确定这五个基因中的过量、罕见、功能破坏性变异在RDS婴儿中的代表性是否高于在知情同意的情况下获得的DNA样本中没有RDS的婴儿（N=940名非洲和欧洲血统的婴儿）。第三，我们将使用基于细胞的功能测定来研究这些破坏性变体的潜在生物学机制。这种全面的研究策略是新颖的，因为我们将以更高的分辨率研究候选基因，使用基于软件的算法来评估变体功能，使用传统的（回归）和新的（Collapsing方法，BimBam，逻辑回归）统计方法来评估变体相互作用，并使用基于细胞的测定来研究已鉴定变体和变体组合的功能。基于细胞的检测方法的发展将允许通过统计学关联识别的变体的机制研究，并为受影响婴儿的诊断和治疗方法的长期发展提供基础。结合我的临床经验，先前的遗传流行病学教学和指导培训，以及一个综合培训计划，使我能够发展使用替代细胞系统的技能，将使我能够发展成为一名独立的研究者，能够将统计观察与功能机制联系起来，并将这些发现转化为RDS婴儿的特定治疗方法。