Regulation of lipid metabolism in pulmonary Type 2 cells

肺2型细胞脂质代谢的调节

基本信息

批准号：
10002619
负责人：
Itsaso Garcia-Arcos
金额：
$ 43.07万
依托单位：
SUNY DOWNSTATE MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-20 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10002619
关键词：
ABCA3 gene ATP binding cassette transporter 1 Acute Address Adult Agonist Air Alveolar Alveolar Cell Apical Area Breathing Bronchoalveolar Lavage Bronchoalveolar Lavage Fluid Cell Line Cell Separation Cell physiology Cells Cellular Metabolic Process Cholesterol Cholesterol Esters Chronic Chronic Disease Chronic Obstructive Airway Disease Confocal Microscopy Data Disease Ensure Exocytosis Fluorescent Probes Forced expiratory volume function Genes Genetic Genetic Models Genetic Transcription Homeostasis Human Cell Line Impairment In Vitro Knock-out Knockout Mice LDL-Receptor Related Protein 1 Label Lecithin Lipids Lipoprotein Receptor Liquid substance Low Density Lipoprotein Receptor Lung Lung diseases Measures Membrane Metabolic Metabolic Pathway Metabolism Microscopy Minor Modeling Molecular Mus Mutation Pathology Pathway interactions Patients Peptide Hydrolases Phospholipase Phospholipids Plasma Process Proteins Pulmonary Pathology Pulmonary Surfactants Pulmonary function tests Recycling Regulation Research Respiratory physiology Role Route Science Signal Transduction Smoke Surface Tension Tamoxifen Techniques Tissues Transcriptional Regulation Transfection Triglycerides Vital capacity alveolar lamellar body apical membrane cell type experimental study extracellular in vivo innovation knock-down lipid metabolism lipid transport loss of function mRNA Expression novel pressure prevent pulmonary function receptor recruit respiratory small hairpin RNA surfactant surfactant production synthetic enzyme therapeutic target trafficking uptake

项目摘要

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.

表面活性剂不足会损害多发性肺疾病的肺顺应性和呼吸功能病理学。我们对成人肺部疾病中表面活性剂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，我们生成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 (LRP1) 治疗成人疾病中的表面活性剂不足特别是在产生表面活性剂的 2 型细胞 (T2C) 中。 LRP1 与呼吸功能下降有关 COPD患者，还具有脂蛋白受体和细胞外蛋白酶清除受体的作用。研究在我们生成的 LRP1 敲除 T2C (LRP1 KD) 和他莫昔芬诱导的 T2C 特异性 LRP1 敲除小鼠中 (SPC-LRP1-/-) 表明 LRP1 是维持表面活性剂脂质分泌和循环体内平衡所必需的确保最佳的肺顺应性和呼吸功能。我们假设 LRP1 控制表面活性剂 T2C 中的代谢，我们将研究其调节机制。在目标 1 中，我们将破译其机制 LRP1 在 T2C 膜水平上的作用以及产生表面活性剂的酶活性的调节 LRP1 影响细胞内脂质代谢运输。在目标 2 中，我们将研究 LRP1 在根尖中的作用 T2C 膜和内体途径中表面活性剂再循环的调节。该提案在理念和技术上均具有创新性。 LRP1在肺表面活性物质中的功能是未知。 LRP1通过不同组织中的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。另外，我们用新颖的技术，包括诱导型和细胞特异性基因敲除模型和组学分析。表面活性剂体内平衡能够维持基本的肺功能，但成人疾病中表面活性剂体内平衡的调节是很少有人理解。表面活性剂代谢失调可能会通过减少表面活性剂代谢来参与并加剧疾病肺顺应性。表面活性剂脂质这一事实进一步强调了这项研究的意义多种肺部病变（包括最常见的病变）的成分发生改变。