Regulation of lipid metabolism in pulmonary Type 2 cells

肺2型细胞脂质代谢的调节

• 批准号: 10367413
• 负责人: Itsaso Garcia-Arcos
• 金额: $ 56.26万
• 依托单位: SUNY DOWNSTATE MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-20 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10367413
• 关键词: A549; ABCA3 gene; ATP binding cassette transporter 1; Acute; Address; Adipose tissue; Adult; Agonist; Air; Alveolar; Alveolar Cell; Anti-Inflammatory Agents; Apical; Area; Bleomycin; Bronchoalveolar Lavage; Cell Culture System; Cell Differentiation process; Cell Line; Cell physiology; Cells; Cholesterol; Cholesterol Esters; Chronic Disease; Chronic Obstructive Pulmonary Disease; Chronic lung disease; Coculture Techniques; Collagen; Complex; Data; Defect; Deposition; Development; Diagnosis; Disease; Down-Regulation; Electron Microscopy; Ensure; Epithelial; Event; Fibroblasts; Fibrosis; Foundations; Gene Expression; Genetic; Genetic Models; Genetic Transcription; Hepatic; Homeostasis; Human; Hydrolysis; In Vitro; Inflammation; Inflammatory; Interleukin-1 beta; Intervention; Knock-out; Knockout Mice; Knowledge; LDL-Receptor Related Protein 1; Lecithin; Lipids; Lipoprotein (a); Lipoprotein Receptor; Lipoproteins; Liquid substance; Low Density Lipoprotein Receptor; Lung; Lung diseases; Measures; Mediating; Membrane; Mesenchymal; Metabolic; Metabolic Pathway; Metabolism; Molecular; Morphology; Mus; Outcome; PPAR alpha; PPAR gamma; Pathology; Pathway Analysis; Pathway interactions; Patients; Peptide Hydrolases; Peroxisome Proliferator-Activated Receptors; Phenotype; Phospholipids; Process; Proteins; Proteomics; Pulmonary Fibrosis; Pulmonary Pathology; Pulmonary Surfactants; Pulmonology; Regulation; Research; Respiratory physiology; Role; Science; Serpins; Signal Transduction; Smooth Muscle Myocytes; Source; Surface Tension; Surfactant therapy; Tamoxifen; Techniques; Testing; Tissues; Tracer; Vital capacity; Work of Breathing; adipocyte differentiation; alveolar epithelium; alveolar lamellar body; cytokine; extracellular; idiopathic pulmonary fibrosis; in vivo; in vivo Model; innovation; intercellular communication; knock-down; lipid biosynthesis; lipid mediator; lipid metabolism; lipidomics; mRNA Expression; macrophage; novel; novel therapeutic intervention; novel therapeutics; prevent; pulmonary arterial hypertension; pulmonary function; receptor; response; restoration; single-cell RNA sequencing; small hairpin RNA; surfactant; surfactant deficiency; surfactant production; surfactant replacement therapy; synthetic enzyme; therapeutic target; transcriptome sequencing; transcriptomics; uptake

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 (AEC2). LRP1 functions as lipoprotein receptor and extracellular protease clearing receptor and it is associated with decreased respiratory function in patients with COPD and pulmonary arterial hypertension. Studies in our generated cell line of LRP1 knockdown AEC2 (LRP1 KD) and tamoxifen-inducible AEC2-specific LRP1 knockout mice (SPC-LRP1-/-) show that LRP1 is required to maintain surfactant lipid secretion and intracellular lipid homeostasis to ensure optimal pulmonary compliance and respiratory function. We hypothesize that LRP1 controls surfactant metabolism in AEC2 and we will study the regulatory mechanisms. In Aim 1 we will decipher the mechanism of action of LRP1 at the membrane level in AEC2 and its regulation of the lipid source for surfactant synthesis in AEC2. In Aim 2 we will investigate the epithelial to mesenchymal cross talk and the role of LRP1 in the progressive decline in lung function during profibrotic challenges and molecular mechanisms responsible. We will attempt a new therapeutic approach to stop the decline. This proposal is innovative conceptually and technically. The role of AEC2 lipid metabolism during adult pulmonary disease 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 in vivo lipid tracing and -omics analysis. Surfactant homeostasis enables basic pulmonary function, but the regulation of surfactant homeostasis in adult disease is very little understood. The significance of this research is further underscored by the fact that surfactant lipid is altered in multiple pulmonary pathologies, including the most prevalent ones.

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(AEC2)中。LRP1作为脂蛋白受体和细胞外的功能 蛋白水解酶清除受体及其与COPD患者呼吸功能下降的关系 肺动脉高压。我们建立的LRP1基因敲除AEC2(LRP1 KD)细胞系的研究 他莫昔芬诱导的AEC2特异性LRP1基因敲除小鼠(SPC-LRP1-/-)显示LRP1需要维持 表面活性物质脂质分泌和细胞内脂质稳态，以确保最佳的肺顺应性和 呼吸功能。我们假设LRP1控制AEC2中的表面活性物质代谢，我们将研究 监管机制。在目标1中，我们将破译LRP1在膜水平上的作用机制 AEC2及其对AEC2合成表面活性物质脂源的调节。在目标2中，我们将调查 肺上皮至间充质的信号传导及LRP1在慢性肺功能进行性下降中的作用 促纤维化的挑战和相关的分子机制。我们将尝试一种新的治疗方法 止住跌势。 这一建议在理念和技术上都是创新的。AEC2在成人脂代谢中的作用 肺部疾病是未知的。LRP1通过脂代谢调节多种细胞功能 组织和我们的研究表明，它还通过表面活性物质脂代谢调节肺功能。在……里面 此外，我们使用了新的技术，包括体内脂质中可诱导的和细胞特异性的基因敲除模型 追踪和组学分析。表面活性物质的动态平衡使基本的肺功能，但调节 表面活性物质在成人疾病中的动态平衡知之甚少。本研究的意义在于 突出的事实是，表面活性物质脂质在多种肺部病理中发生改变，包括大多数 流行的一种。