Interstitial lung diseases (ILD) due to disturbed processing and function of the lipid transporter ABCA3 as a result of mutations in the ABCA3 gene

由于 ABCA3 基因突变，脂质转运蛋白 ABCA3 的加工和功能受到干扰，导致间质性肺疾病 (ILD)

• 批准号: 226491218
• 负责人: Professor Dr. Matthias Griese
• 金额: --
• 依托单位: Kinderklinik und Kinderpoliklinik im Dr. von Haunerschen Kinderspital
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/226491218?language=en
• 关键词: Interstitial; lung; diseases; ILD; due

The lipid transporter ABCA3 is indispensable for the biogenesis of lamellar bodies in alveolar type II cells and for the production of pulmonary surfactant. A reduced or missing activity of ABCA3 due to mutations causes acute respiratory distress syndrome in neonates and chronic interstitial lung disease in children and young adults. Therefore, therapeutic approaches must be aimed at increasing ABCA3 activity in the lung.The project we are suggesting for funding is dealing with factors regulating the physiological function of normal and mutant ABCA3. We plan to investigate the mechanisms that determine the amount of ABCA3 in the lamellar body membrane. Among these are the trafficking and posttranslational regulation of the protein. Another focus of our studies is the question how clinically relevant mutations affect these mechanisms. In addition, the effects of mutations on ABCA3 activity will be analyzed using lipidomics and also by the use of a new class of phosphatidylcholine derivatives that resemble the naturally occurring substrates more closely than most compounds that have been used so far. To be able to precisely analyze mutation effects we generate an ABCA3 knockout cell line using zinc-finger nuclease technology. In addition to in vitro studies, we plan to analyze the amount and localization of ABCA3 in lung tissue from patients with ABCA3 mutations, thereby establishing a link between in vitro data and clinical phenotype. The correlation of in vitro findings with ex vivo data from lung tissue of patients with ABCA3 mutations will facilitate new approaches for therapeutic interventions aimed at increasing functional activity of ABCA3 in the lung.From the project we suggest for funding herein we expect new insights into function and regulation of ABCA3, their disturbance as a result of ABCA3 mutations and new experimental approaches for their correction. These findings will facilitate new therapeutic approaches for the modulation of ABCA3 function. Moreover, an improved understanding of the cell biology of ABCA3 will also allow conclusions regarding other members of the ABCA-family whose cell biology is largely unknown.

脂质转运蛋白ABCA 3对于肺泡II型细胞中板层体的生物发生和肺表面活性物质的产生是必不可少的。由于突变导致的ABCA3活性降低或缺失导致新生儿急性呼吸窘迫综合征和儿童和年轻人慢性间质性肺病。因此，治疗方法必须针对增加ABCA 3在肺中的活性。我们建议资助的项目是处理调节正常和突变ABCA 3生理功能的因素。我们计划研究决定板层体膜中ABCA 3量的机制。其中包括蛋白质的运输和翻译后调节。我们研究的另一个重点是临床相关突变如何影响这些机制的问题。此外，突变对ABCA3活性的影响将使用脂质组学进行分析，并使用一类新的磷脂酰胆碱衍生物，这些衍生物比迄今为止使用的大多数化合物更接近天然存在的底物。为了能够精确地分析突变效应，我们使用锌指核酸酶技术产生ABCA 3敲除细胞系。除了体外研究，我们计划分析ABCA3突变患者肺组织中ABCA3的数量和定位，从而建立体外数据和临床表型之间的联系。ABCA3突变患者肺组织的体外研究结果与离体数据的相关性将促进旨在增加ABCA3在肺中的功能活性的治疗干预的新方法。从我们建议在此资助的项目中，我们期望对ABCA3的功能和调节的新见解，ABCA3突变导致的ABCA3功能紊乱和新的校正实验方法。这些发现将促进调节ABCA 3功能的新治疗方法。此外，对ABCA 3细胞生物学的进一步理解也将允许关于ABCA家族其他成员的结论，其细胞生物学在很大程度上是未知的。

项目成果

Neonatal Respiratory Insufficiency Caused by an (Homozygous) ABCA3-Stop Mutation: a Systematic Evaluation of Therapeutic Options

由（纯合）ABCA3-Stop 突变引起的新生儿呼吸功能不全：治疗方案的系统评估

• DOI: 10.1055/s-0033-1363687
• 发表时间: 2014
• 期刊: Klinische Pädiatrie
• 作者: Winter J;Essmann S;Kidszun A;Aslanidis C;Griese M;Poplawska K;Bartsch M;Schmitz G;Mildenberger E
• 通讯作者: Mildenberger E