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.

表面活性剂功能不全损害多种肺部的肺合顺顺和呼吸功能病理。我们对成年肺疾病中表面活性剂代谢的理解非常有限，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）的表面活性剂不足特别是在产生2型细胞（T2C）的表面活性剂中。 LRP1与呼吸功能降低有关 COPD患者，它也充当脂蛋白受体和细胞外蛋白酶清除受体。研究在我们生成的LRP1敲低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必须维持表面活性剂脂质分泌和回收稳态至确保最佳的肺合顺顺和呼吸功能。我们假设LRP1控制表面活性剂 T2C中的代谢，我们将研究调节机制。在AIM 1中，我们将破译 LRP1在T2C中的膜水平和表面活性剂产生酶活性的调节和 LRP1的细胞内脂质代谢运输。在AIM 2中，我们将研究LRP1在顶端的作用 T2C的膜和内体途径中表面活性剂回收的调节。该建议在概念和技术上都是创新的。 LRP1在肺表面活性剂中的功能是未知。 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来调节肺功能。此外，我们使用小说包括诱导型和细胞特异性遗传基因敲除模型和 - 组分析的技术。表面活性剂稳态可以实现基本的肺功能，但是表面活性剂稳态在成人疾病中的调节是很少理解。表面活性剂代谢的放松管制可能会通过减少肺合规。表面活性剂脂质的事实进一步强调了这项研究的意义在包括最普遍的多种肺部病理学中，组成发生了变化。