Role of SREBP Network in Surfactant Lipid Homeostasis and Lung Maturation

SREBP 网络在表面活性剂脂质稳态和肺成熟中的作用

• 批准号: 8693002
• 负责人: YAN XU
• 金额: $ 44.84万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8693002
• 关键词: Adult; Adult Respiratory Distress Syndrome; Air; Algorithms; Alveolar; Area; Binding; Binding Proteins; Bioinformatics; Biological; Biological Models; Biology; Birth; Breathing; CEBPA gene; Cells; Child; Cholesterol; Cholesterol Homeostasis; Chronic lung disease; Clinical; Communities; Complex; Complex Mixtures; Computing Methodologies; Data; Data Set; Databases; Defect; Development; Diagnosis; Diagnostic Reagent; Disease; Disease Marker; Economic Inflation; Epithelial Cells; Epithelium; Fatty Acids; Fetal Lung; Financial compensation; Gases; Gene Expression; Gene Targeting; Genes; Genetic; Glucocorticoids; Goals; Homeostasis; In Vitro; Inbred Strains Mice; Infection; Injury; Insulin; Intensive Care; Interdisciplinary Study; Knock-out; Lecithin; Length; Lipids; Location; Lung; Lung diseases; Messenger RNA; Metabolism; Molecular; Morbidity - disease rate; Morphology; Mouse Strains; Mus; Newborn Respiratory Distress Syndrome; Pathway Analysis; Perinatal; Physiological; Premature Infant; Process; Processed Genes; Production; Proteins; Proteolysis; Pulmonary Surfactants; Regulation; Regulator Genes; Regulatory Element; Research; Respiratory physiology; Role; SCAP protein; Signal Pathway; Signal Transduction; Small Interfering RNA; Staging; Sterols; Stream; System; Systems Biology; Tars; Testing; Therapeutic; Therapeutic Intervention; Time; Transgenic Mice; Tweens; alveolar lamellar body; base; computer based statistical methods; data integration; experience; gene synthesis; genome-wide; in vivo; innovation; lung maturation; mortality; mouse model; network models; novel; premature; prenatal; prevent; programs; protein activation; respiratory; respiratory distress syndrome; response; small hairpin RNA; surfactant; surfactant deficiency; therapeutic target; Adult; Adult Respiratory Distress Syndrome; Air; Algorithms; Alveolar; Area; Binding; Binding Proteins; Bioinformatics; Biological; Biological Models; Biology; Birth; Breathing; CEBPA gene; Cells; Child; Cholesterol; Cholesterol Homeostasis; Chronic lung disease; Clinical; Communities; Complex; Complex Mixtures; Computing Methodologies; Data; Data Set; Databases; Defect; Development; Diagnosis; Diagnostic Reagent; Disease; Disease Marker; Economic Inflation; Epithelial Cells; Epithelium; Fatty Acids; Fetal Lung; Financial compensation; Gases; Gene Expression; Gene Targeting; Genes; Genetic; Glucocorticoids; Goals; Homeostasis; In Vitro; Inbred Strains Mice; Infection; Injury; Insulin; Intensive Care; Interdisciplinary Study; Knock-out; Lecithin; Length; Lipids; Location; Lung; Lung diseases; Messenger RNA; Metabolism; Molecular; Morbidity - disease rate; Morphology; Mouse Strains; Mus; Newborn Respiratory Distress Syndrome; Pathway Analysis; Perinatal; Physiological; Premature Infant; Process; Processed Genes; Production; Proteins; Proteolysis; Pulmonary Surfactants; Regulation; Regulator Genes; Regulatory Element; Research; Respiratory physiology; Role; SCAP protein; Signal Pathway; Signal Transduction; Small Interfering RNA; Staging; Sterols; Stream; System; Systems Biology; Tars; Testing; Therapeutic; Therapeutic Intervention; Time; Transgenic Mice; Tweens; alveolar lamellar body; base; computer based statistical methods; data integration; experience; gene synthesis; genome-wide; in vivo; innovation; lung maturation; mortality; mouse model; network models; novel; premature; prenatal; prevent; programs; protein activation; respiratory; respiratory distress syndrome; response; small hairpin RNA; surfactant; surfactant deficiency; therapeutic target

DESCRIPTION (provided by applicant): Pulmonary surfactant is essential for gas exchange and required for adaptation to air breathing at birth and thereafter. Defects in the surfactant system are known to be associated with common pulmonary disorders including neonatal respiratory distress syndrome, a major cause of mortality and morbidity in preterm infants. Little is known regarding the genetic regulation of the surfactant system, in particular the genes and associated transcriptional networks serve to induce the critical physiological program at birth. Our long-term goal is to prevent and control common pulmonary disorders associated with surfactant deficiency including neonatal respiratory distress syndrome and acute respiratory distress syndrome in children and adults. The objective of this application is to integrate computational and experimental approaches to identify critical regulators of surfactant lipid homeostasis during lung maturation. This application seek to test the central hypothesis that SREBP (sterol regulatory element binding protein) signaling is a key component in the transcriptional network sensing and regulating genes and processes critical for surfactant homeostasis during lung maturation. We plan to accomplish our objective by pursuing the following three Specific Aims: 1). Identify a transcriptional network controlling perinatal surfactant lipid homeostasis; 2). Determine the mechanisms by which SREBP influences perinatal lung lipid homeostasis; and 3) Determine the critical perinatal regulatory components in the SREBP network. Under Aim 1, we will develop and refine a transcriptional network controlling surfactant lipid homeostasis during lung maturation. In Aim 2, we will determine and evaluate the direct vs. compensatory roles of SREBP in perinatal lung in vivo using SREBP deletion/activation transgenic mouse models. In Aim 3, we will validate biological relevant upstream and downstream genes in SREBP centered signaling pathway in vivo and in vitro. The experimental results will be used to further refine the transcriptional network. The project is highly innovative, new algorithms will be developed for data integration and network model refinement; newly developed transgenic mouse models and highly refined lung mRNA microarray data from mouse strains with distinct lung maturation programs will be used, from which, a dynamic transcriptional network controlling perinatal lung surfactant lipid homeostasis will be constructed for the first time in surfactant biology. The proposed research is significant, a comprehensive understanding of the transcriptional program controlling perinatal lung surfactant level will provide scientific basis for development of diagnostic reagents, disease markers and therapeutic interventions aimed at preventing or ameliorating pulmonary mortality and morbidity associated with surfactant deficiency. The synergistic integration of computational and experimental approaches developed in this application will be highly relevant to studies related to many other research areas. The microarray datasets and network models we developed will benefit the scientific community at large.

描述（由申请人提供）：肺表面活性剂对于气体交换是必不可少的，因此需要在出生时和此后适应空气呼吸。已知表面活性剂系统中的缺陷与包括新生儿呼吸窘迫综合征在内的常见肺部疾病有关，这是早产儿死亡率和发病率的主要原因。关于表面活性剂系统的遗传调节，尤其是基因和相关的转录网络来诱导关键生理程序时，知之甚少。我们的长期目标是预防和控制与表面活性剂缺乏症有关的常见肺部疾病，包括儿童和成人的新生儿呼吸窘迫综合征和急性呼吸窘迫综合征。该应用的目的是整合计算和实验方法，以确定肺部成熟过程中表面活性剂脂质稳态的关键调节剂。该应用旨在检验中心假设：SREBP（固醇调节元件结合蛋白）信号传导是转录网络感测和调节基因和过程对肺部成熟过程中表面活性剂稳态至关重要的过程的关键组成部分。我们计划通过追求以下三个特定目标来实现我们的目标：1）。确定控制围产期表面活性剂脂质稳态的转录网络； 2）。确定SREBP影响围产期肺脂质稳态的机制； 3）确定SREBP网络中关键的围产期调节组件。在AIM 1下，我们将开发和完善一个转录网络，以控制肺部成熟期间表面活性剂脂质稳态。在AIM 2中，我们将使用SREBP缺失/激活转基因小鼠模型来确定和评估SREBP在体内围产期肺中的直接和补偿作用。在AIM 3中，我们将在体内和体外验证SREBP中心信号通路中的生物学相关上游基因和下游基因。实验结果将用于进一步完善转录网络。该项目具有很高的创新性，将开发新的算法来进行数据集成和网络模型改进；将使用新开发的转基因小鼠模型和具有不同肺成熟程序的小鼠菌株的高度精制的肺mRNA微阵列数据，从中，将首次在表面活性剂生物学中首次构建一个动态转录网络，该动态转录网络控制围产期肺部表面活性剂脂质稳态。拟议的研究是重要的，对控制围产期肺部表面活性剂水平的转录程序的全面了解将为开发诊断试剂，疾病标志物和治疗干预措施的发展提供科学基础，旨在预防或减轻与表面活性剂缺乏症相关的肺部死亡率和发病率。本应用程序中开发的计算和实验方法的协同整合将与与许多其他研究领域相关的研究高度相关。我们开发的微阵列数据集和网络模型将使整个科学界受益。