Regulation of lipid metabolism in pulmonary Type 2 cells

肺表面活性物质缺乏对多发性肺疾病患者肺顺应性和呼吸功能的影响 病理学。我们对成人肺部疾病中表面活性物质代谢的了解非常有限，这 限制了治疗靶向的潜力。在这个项目中，我们已经生成了一种新的遗传模型 成人疾病中肺表面活性物质缺乏与低密度脂蛋白受体相关蛋白1(LRP1)的缺失 特别是在产生表面活性物质的2型细胞(T2C)中。LRP1与呼吸功能下降有关 它还具有脂蛋白受体和胞外蛋白水解酶清除受体的功能。研究 在我们建立的LRP1基因敲除T2C(LRP1 KD)和他莫昔芬诱导的T2C特异性LRP1基因敲除小鼠中 (SPC-LRP1-/-)表明LRP1是维持表面活性物质脂质分泌和循环内稳态所必需的，以 确保最佳的肺顺应性和呼吸功能。我们假设LRP1控制着表面活性物质 在T2C中的代谢，我们将研究其调节机制。在目标1中，我们将破译 LRP1在T2C细胞膜水平上的作用及对产生表面活性物质的酶活性和 LRP1细胞内脂代谢转运的研究。在目标2中，我们将研究LRP1在根尖细胞中的作用。 T2C膜和内体途径中表面活性物质循环的调节。 这一建议在理念和技术上都是创新的。LRP1在肺表面活性物质中的作用 未知。LRP1通过不同组织中的脂代谢调节多种细胞功能 表明它还通过表面活性物质脂代谢调节肺功能。此外，我们还使用小说 包括可诱导和细胞特异性基因敲除模型和组学分析在内的技术。表面活性剂 动态平衡使基本的肺功能得以实现，但成人疾病中表面活性物质动态平衡的调节是 鲜为人知。表面活性物质代谢的放松调控可能会通过减少 肺顺应性。这项研究的意义进一步强调了表面活性物质脂质的事实 在包括最常见的肺部病变在内的多种肺部病变中，其成分都会发生改变。

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.