ABCA3 and the Response to Lung Injury

ABCA3 和对肺损伤的反应

基本信息

批准号：
7824312
负责人：
RASHMIN C SAVANI
金额：
$ 1.57万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7824312
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 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 public health relevance receptor reconstitution research study respiratory distress syndrome response surfactant surfactant deficiency trafficking

项目摘要

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结合纸盒转运蛋白ABCA3中的突变与新生儿的致命表面活性剂缺乏和呼吸窘迫综合征（RDS）以及大儿童和成人的间隙肺部疾病有关。 ABCA3位于层状体的极限膜中，对于层状体发生和肺泡2型上皮细胞中磷脂的转运至关重要。 ABCA3突变构成了越来越多的称为“构象疾病”的疾病的一部分，其中突变蛋白被错误折叠，保留在内质网中（ER）并因泛素蛋白酶体降解而降解。当这种质量控制系统不堪重负时，突变蛋白会积聚在ER中，并触发应力和其他蛋白质的激活/表达（ER应激）。某些ABCA3运输突变体可以通过蛋白质伴侣在体外挽救，从而促进适当的折叠和改善的贩运。我们最近证明，尽管ABCA3小鼠磷脂的合成降低，但它们存活到成年，而ABCA3 - / - 小鼠无法形成层状体，但成熟的SP-B的表达受到干扰，它们的肺部未能膨胀，并且在出生后很快死亡。我们使用具有与人类疾病相关的突变的纯合无效小鼠的转基因重建，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潜在的治疗疗法，以限制不良反应。我们假设小鼠中ABCA3人类突变的表达将提供人类疾病模型，并且杂合子和突变的ABCA3小鼠更容易受到博霉素和高氧诱导的肺损伤的影响。此外，我们假设ABCA3突变与透明质酸（HA）及其受体的增加相关，从而促进巨噬细胞积累，并且可以使用抗HA或受体策略来改善巨噬细胞的积累。具体目标1将确定野生型和ABCA3的反应，以及有条件表达野生型或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ABCA3 - / - 小鼠与WT或ABCA3突变重构的II型牙槽II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，以便它们对ER应力反应的影响。具体目标3将确定伴侣和抗HA/受体方法对与WT或ABCA3突变重构的小鼠对博来霉素或高氧诱导的肺损伤的反应的影响。公共卫生相关性：ABCA3转运蛋白基因中的突变会导致多种肺部疾病，导致直接新生儿时期死亡或儿童慢性肺部疾病并成年。我们想开发该基因中人类突变的小鼠模型，以研究其对肺损伤的易感性，疾病机制和测试潜在疗法。由于它们与肺损伤后的炎症有关，因此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。我们认为，来自这些研究的数据将对遗传肺疾病的发病机理产生影响，并在潜在疗法的发展中提供重要信息。此外，这些研究的发现将与具有相似疾病机理的肺（例如囊性纤维化）和肝脏（例如α-1-抗抗蛋白酶缺乏症）有关。