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

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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.