Regulation of lipid metabolism in pulmonary Type 2 cells

肺表面活性物质不足损害肺顺应性和呼吸功能 病理学我们对成人肺疾病中表面活性物质代谢的了解非常有限， 限制了治疗靶向的潜力。在这个项目中，我们已经产生了一个新的遗传模型， 通过删除低密度脂蛋白受体相关蛋白1（LRP 1）导致成人疾病中的表面活性物质不足 特别是在产生表面活性剂的2型细胞（T2 C）中。LRP 1与呼吸功能下降相关， COPD患者中，它也作为脂蛋白受体和细胞外蛋白酶清除受体发挥作用。研究 在我们产生的LRP 1敲除T2 C（LRP 1 KD）和他莫昔芬诱导的T2 C特异性LRP 1敲除小鼠中， （SPC-LRP 1-/-）显示LRP 1是维持表面活性剂脂质分泌和再循环稳态所必需的， 确保最佳的肺顺应性和呼吸功能。我们假设LRP 1控制表面活性剂 T2 C代谢，我们将研究调控机制。在目标1中，我们将破译 LRP 1在T2 C中膜水平的作用和产生表面活性剂的酶活性的调节， LRP 1的细胞内脂质代谢运输。在目标2中，我们将研究LRP 1在根尖细胞中的作用。 T2 C膜和调节内体途径中的表面活性剂再循环。 这一建议在概念上和技术上都是创新的。LRP 1在肺表面活性物质中的作用 未知LRP 1在不同组织中通过脂质代谢调节许多细胞功能，我们的研究 表明它还通过表面活性剂脂质代谢调节肺功能。此外，我们还使用了新的 技术，包括诱导型和细胞特异性基因敲除模型和组学分析。表面活性 体内平衡使基本的肺功能，但在成人疾病的表面活性物质的体内平衡的调节， 很少有人理解。表面活性物质代谢失调可能通过减少 肺顺应性这项研究的意义进一步强调了表面活性剂脂质 在多种肺部病理中，包括最常见的肺部病理，其组成发生改变。

Surfactant insufficiency compromises pulmonary compliance and respiratory function in multiple pulmonary pathologies. Our understanding of surfactant metabolism in adult pulmonary disease is very limited and this restricts the potential for therapeutic targeting. In this project, we have generated a new genetic model of surfactant insufficiency in adult disease by deleting the low density lipoprotein receptor related protein 1 (LRP1) specifically in surfactant producing type 2 cells (T2C). LRP1 is associated with decreased respiratory function in COPD patients, and it also functions as lipoprotein receptor and extracellular protease clearing receptor. Studies in our generated LRP1 knockdown T2C (LRP1 KD) and tamoxifen-inducible T2C-specific LRP1 knockout mice (SPC-LRP1-/-) show that LRP1 is required to maintain surfactant lipid secretion and recycling homeostasis to ensure optimal pulmonary compliance and respiratory function. We hypothesize that LRP1 controls surfactant metabolism in T2C and we will study the regulatory mechanisms. In Aim 1 we will decipher the mechanism of action of LRP1 at the membrane level in T2C and the regulation of surfactant-producing enzymatic activities and of intracellular lipid metabolic trafficking by LRP1. In Aim 2 we will investigate the role of LRP1 in the apical membrane of T2C and the regulation of surfactant recycling in the endosomal route. This proposal is innovative conceptually and technically. The function of LRP1 in pulmonary surfactant is unknown. LRP1 regulates many cellular functions through lipid metabolism in different tissues and our study shows that it also regulates pulmonary function through surfactant lipid metabolism. In addition, we use novel techniques that include inducible and cell-specific genetic knockout models and -omics analysis. Surfactant homeostasis enables basic pulmonary function, but the regulation of surfactant homeostasis in adult disease is very little understood. Deregulation of surfactant metabolism may partake and exacerbate disease by decreasing pulmonary compliance. The significance of this research is further underscored by the fact that surfactant lipid composition is altered in multiple pulmonary pathologies, including the most prevalent ones.