ABCA3 and the Response to Lung Injury

ABCA3 和对肺损伤的反应

• 批准号: 8210911
• 负责人: RASHMIN C SAVANI
• 金额: $ 38.86万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8210911
• 关键词: AGTR2 gene; ATP-Binding Cassette Transporters; Acids; Adult; Adverse effects; Alveolar; Binding; Birth; Bleomycin; Blocking Antibodies; CD44 Antigens; CD44 gene; Cells; Cessation of life; Chemicals; Child; Childhood; Chronic lung disease; Data; Development; Disease; Endoplasmic Reticulum; Epithelial Cells; Extracellular Matrix; Failure; Fibrosis; Genes; Genetic; Glycosaminoglycans; Health; Heterozygote; Human; Human Genetics; Hyaluronan; Hyaluronic Acid; Hyperoxia; In Vitro; Inflammation; Injury; Interstitial Lung Diseases; Knockout Mice; Liver; Lung; Lung diseases; Lysosomes; Membrane; Modeling; Molecular Chaperones; Morphology; Mus; Mutation; Neonatal; Newborn Infant; Newborn Respiratory Distress Syndrome; Pathogenesis; Peptides; Phenotype; Phospholipids; Predisposition; Process; Proteins; Publishing; Pulmonary Surfactant-Associated Protein B; Quality Control; Resolution; Respiratory distress; Role; Secretory Vesicles; Stress; System; Testing; Therapeutic; Transgenic Mice; Transgenic Organisms; alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency; alveolar lamellar body; alveolar type II cell; biological adaptation to stress; endoplasmic reticulum stress; human HMMR protein; human disease; improved; insight; interest; liver cystic fibrosis; lung injury; macrophage; mortality; mouse model; mutant; neonatal death; neonate; receptor; reconstitution; research study; respiratory distress syndrome; response; surfactant; surfactant deficiency; trafficking

DESCRIPTION (provided by applicant): Mutations in the ATP-binding cassette transporter ABCA3 are associated with fatal surfactant deficiency and Respiratory Distress Syndrome (RDS) in neonates, and interstitial lung disease in older children and adults. Located in the limiting membrane of lamellar bodies, ABCA3 is critical for lamellar body genesis and the transport of phospholipid in alveolar type 2 epithelial cells. ABCA3 mutations form part of a growing number of diseases termed "conformational disorders" in which the mutant protein is misfolded, retained in the endoplasmic reticulum (ER) and degraded by ubiquitinproteosome degradation. When this quality control system is overwhelmed, mutant protein accumulates in the ER and triggers the activation/expression of stress and other proteins (ER Stress). Certain ABCA3 trafficking mutants can be rescued in vitro by protein chaperones that promote appropriate folding and improved trafficking. We have recently demonstrated that although ABCA3 mice have decreased phospholipid synthesis, they survive to adulthood, and ABCA3-/- mice fail to form lamellar bodies, the expression of mature SP-B is disrupted, their lungs fail to inflate and they die soon after birth. Using transgenic reconstitution of homozygous null mice with wild type or ABCA3 with mutations associated with human disease, we intend to develop mouse models of the human disease, determine their response to lung injury and test potential therapeutics for limiting adverse effects. We hypothesize that expression of human mutations of ABCA3 in mice will provide a model of human disease, and that heterozygous and mutant ABCA3 mice will be more susceptible to bleomycin- and hyperoxia-induced lung injury. Further, we hypothesize that ABCA3 mutations are associated with increases in hyaluronan (HA) and its receptors that promote macrophage accumulation, and which can be ameliorated using anti-HA or -receptor strategies. Specific Aim 1 will determine the response of wild type and ABCA3, as well as mice with conditional expression of wild type or ABCA3 mutations, to bleomycin- and hyperoxia-induced lung injury. Specific Aim 2 will examine alveolar type II cells isolated from ABCA3-/- mice reconstituted with WT or ABCA3 mutations to determine lamellar body morphology, the presence of ER stress response, and will test chemical chaperones and anti-HA/receptor approaches for their effects on the ER stress response. Specific Aim 3 will determine the effects of chaperones and anti-HA/receptor approaches on the response to bleomycin- or hyperoxia-induced lung injury in mice reconstituted with WT or ABCA3 mutations. PUBLIC HEALTH RELEVANCE: Mutations in the gene for the ABCA3 transporter cause a variety of lung diseases that result in either death in the immediate newborn period or chronic lung disease in children and into adulthood. We want to develop mouse models of the human mutations in this gene so as to study their susceptibility to lung injury, the mechanisms of disease, and to test potential therapies. Since they have been implicated in inflammation after lung injury, we are also interested in studying the role of the extracellular matrix molecule hyaluronan (HA) and its receptors in the disease processes associated with ABCA3 mutations. We believe that the data from these studies will have implications for the pathogenesis of genetic lung diseases as well as provide vital information in the development of potential therapies. Further, the findings emanating from these studies will be relevant to other severe conditions of the lung (e.g. cystic fibrosis) and liver (e.g. alpha-1-antitrypsin deficiency) that have similar mechanisms of disease.

描述（由申请人提供）：ATP 结合盒转运蛋白 ABCA3 的突变与致命的表面活性剂缺乏和新生儿呼吸窘迫综合征 (RDS) 以及年龄较大儿童和成人的间质性肺病有关。 ABCA3 位于板层体的限制膜中，对于板层体的发生和 2 型肺泡上皮细胞中磷脂的运输至关重要。 ABCA3 突变是越来越多被称为“构象障碍”的疾病的一部分，其中突变蛋白被错误折叠，保留在内质网 (ER) 中并被泛素蛋白酶体降解而降解。当该质量控制系统不堪重负时，突变蛋白会在 ER 中积聚并触发应激和其他蛋白的激活/表达（ER 应激）。某些 ABCA3 运输突变体可以在体外通过促进适当折叠和改善运输的蛋白质伴侣来拯救。我们最近证明，虽然ABCA3小鼠磷脂合成减少，但它们能存活到成年，而ABCA3-/-小鼠不能形成板层体，成熟SP-B的表达被破坏，它们的肺不能膨胀，出生后很快就死亡。利用带有野生型或带有与人类疾病相关突变的ABCA3的纯合子小鼠的转基因重建，我们打算开发人类疾病的小鼠模型，确定它们对肺损伤的反应，并测试限制不良反应的潜在疗法。我们假设 ABCA3 的人类突变在小鼠中的表达将提供人类疾病的模型，并且杂合和突变的 ABCA3 小鼠将更容易受到博来霉素和高氧诱导的肺损伤。此外，我们假设 ABCA3 突变与促进巨噬细胞积累的透明质酸 (HA) 及其受体的增加有关，并且可以使用抗 HA 或 受体策略来改善。具体目标 1 将确定野生型和 ABCA3 以及条件表达野生型或 ABCA3 突变的小鼠对博来霉素和高氧诱导的肺损伤的反应。具体目标 2 将检查从 WT 或 ABCA3 突变重组的 ABCA3-/- 小鼠中分离的肺泡 II 型细胞，以确定层状体形态、ER 应激反应的存在，并将测试化学伴侣和抗 HA/受体方法对 ER 应激反应的影响。具体目标 3 将确定伴侣和抗 HA/受体方法对 WT 或 ABCA3 突变重建小鼠对博来霉素或高氧诱导的肺损伤反应的影响。公众健康相关性：ABCA3 转运蛋白基因突变会导致多种肺部疾病，导致新生儿期死亡或儿童及成年期慢性肺部疾病。我们希望开发该基因人类突变的小鼠模型，以便研究它们对肺损伤的易感性、疾病机制，并测试潜在的疗法。由于它们与肺损伤后的炎症有关，我们也有兴趣研究细胞外基质分子透明质酸 (HA) 及其受体在与 ABCA3 突变相关的疾病过程中的作用。我们相信，这些研究的数据将对遗传性肺病的发病机制产生影响，并为潜在疗法的开发提供重要信息。此外，这些研究的结果将与具有相似疾病机制的其他严重肺部疾病（例如囊性纤维化）和肝脏疾病（例如α-1-抗胰蛋白酶缺乏症）相关。