ABCA3 and Alveolar Homeostasis

ABCA3 和肺泡稳态

基本信息

批准号：
7642306
负责人：
Jeffrey A Whitsett
金额：
$ 44.2万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-10 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7642306
关键词：
ABCA3 gene Acute Acute respiratory failure Adult Alleles Alveolus Amino Acids Animal Model Applications Grants Autopsy Biochemical Biopsy Birth Breeding Bronchopulmonary Dysplasia Carrier Proteins Cell Line Cell Survival Cell physiology Cells Chronic Chronic lung disease Clinical Research Complex Data Development Diagnosis Diagnostic Disease Doxycycline Endotoxins Epithelial Cells Etiology Failure Functional disorder Gene Deletion Gene Expression Gene-Modified Genes Genetic Genetic Transcription Genomics Goals Homeostasis Human Image Immunohistochemistry In Situ Hybridization In Vitro Inflammation Inherited Injury Integration Host Factors Interstitial Lung Diseases Interstitial Pneumonia Lipids Lung Lung diseases Maintenance Membrane Proteins Messenger RNA Missense Mutation Modeling Molecular Morphology Mouse Strains Mus Mutant Strains Mice Mutate Mutation Oxygen Pathogenesis Pathway interactions Patients Perinatal Physiological Play Pneumonia Point Mutation Predisposition Principal Investigator Process Production Proteins Pulmonary Fibrosis Pulmonary Surfactant-Associated Protein A Pulmonary Surfactants Pulmonary alveolar structure RNA Regulation Research Personnel Respiratory Failure Respiratory physiology Role Route Secondary to Severities Severity of illness Site Specimen Study models Surface Tension System Testing Time Transfection Transgenic Mice Transplanted tissue Type II Epithelial Receptor Cell Variant alveolar homeostasis alveolar lamellar body alveolar type II cell base cell injury design human disease human tissue immunocytochemistry in vitro testing in vivo infancy insertion/deletion mutation lung injury mutant pathogen postnatal programs promoter protein degradation protein function respiratory respiratory distress syndrome response selective expression surfactant trafficking transcription factor

项目摘要

DESCRIPTION (provided by applicant): ABCA3 and the Pathogenesis of Acute and Chronic Lung Disease - This grant application is designed to test the hypotheses that (1) ABCA3 transport protein plays a complex and critical role in alveolar homeostasis, and (2) mutations and deficits in ABCA3 function cause and modify acute and chronic lung disease in infants and adults. The application is based on preliminary data demonstrating that mutations in the human ABCA3 gene cause severe lung disease which varies in time of presentation and severity. In this grant application, we will determine the role of the mouse Abca3 gene in alveolar homeostasis, generating and utilizing mice in which the Abca3 gene has been conditionally deleted in respiratory epithelial cells, creating null or partial deletions of the gene. The molecular and cellular consequences of Abca3 deletion, deficiency, and mutation will be determined in vivo and in vitro. We will assess whether cell-specific effects of selected ABCA3 mutant proteins (associated with human disease) alter routing, stability, and function of the protein. In vivo and in vitro studies will assess whether altered synthesis, routing, and function of the mutant protein cause cell injury that might contribute to the pathogenesis of lung disease. Genes modifying the disorder will be identified in transgenic mice and in cell lines using mRNA microarray analyses. Strain-dependent differences in the severity of lung disease will be assessed after breeding of the Abca3 mutant mice into susceptible and non-susceptible strains of mice. Susceptibility of Abca3 mutant mice to secondary injury by oxygen and endotoxin will be determined in vivo. Expression of the Abca3 gene will be studied at transcriptional and post-transcriptional levels to determine the mechanisms controlling ABCA3 expression. Immunocytochemistry and lung morphology will be correlated with ABCA3 mutations in human tissues. We will test the hypothesis that susceptibility to lung disease at birth, and thereafter, may be influenced by the levels of ABCA3. We will determine the levels of expression of ABCA3 during development and after lung injury in mice. Immunological, biochemical, and structural markers of ABCA3 dysfunction will be sought to enhance our ability to diagnose ABCA3-related lung disease. Long-term goals of this application seek to understand the role of ABCA3 in the pathogenesis of both inherited and acquired lung disease, to identify genes (pathways) modifying disease pathogenesis, and to develop new strategies to enhance ABCA3 function for the treatment of acute and chronic lung disease in humans.

描述（由申请人提供）：ABCA3 和急性和慢性肺病的发病机制 - 该拨款申请旨在测试以下假设：(1) ABCA3 转运蛋白在肺泡稳态中发挥复杂而关键的作用，以及 (2) 突变和ABCA3 功能缺陷会导致和改变婴儿和成人的急性和慢性肺部疾病。该申请基于初步数据，表明人类 ABCA3 基因突变会导致严重的肺部疾病，其发病时间和严重程度各不相同。在本次拨款申请中，我们将确定小鼠 Abca3 基因在肺泡稳态中的作用，生成并利用呼吸道上皮细胞中 Abca3 基因被条件性删除的小鼠，从而产生该基因的无效或部分删除。 Abca3 缺失、缺陷和突变的分子和细胞后果将在体内和体外确定。我们将评估选定的 ABCA3 突变蛋白（与人类疾病相关）的细胞特异性效应是否会改变该蛋白的路径、稳定性和功能。体内和体外研究将评估突变蛋白的合成、路径和功能的改变是否会导致细胞损伤，从而可能导致肺部疾病的发病机制。将使用 mRNA 微阵列分析在转基因小鼠和细胞系中鉴定修饰该疾病的基因。将 Abca3 突变小鼠培育成易感和非易感小鼠品系后，将评估肺病严重程度的品系依赖性差异。将在体内测定 Abca3 突变小鼠对氧气和内毒素继发性损伤的易感性。将在转录和转录后水平上研究 Abca3 基因的表达，以确定控制 ABCA3 表达的机制。免疫细胞化学和肺形态学将与人体组织中的 ABCA3 突变相关。我们将检验这样的假设：出生时及其后对肺部疾病的易感性可能会受到 ABCA3 水平的影响。我们将测定小鼠发育期间和肺损伤后 ABCA3 的表达水平。我们将寻找 ABCA3 功能障碍的免疫学、生化和结构标志物，以增强我们诊断 ABCA3 相关肺部疾病的能力。该应用的长期目标旨在了解 ABCA3 在遗传性和获得性肺病发病机制中的作用，识别改变疾病发病机制的基因（途径），并开发新策略来增强 ABCA3 功能以治疗急性和获得性肺病。人类慢性肺部疾病。