Alveolar Type II Cells in Vitro: Effect of KGF

体外肺泡 II 型细胞：KGF 的作用

基本信息

批准号：
7379943
负责人：
ROBERT James MASON
金额：
$ 37.85万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
财政年份：
1983
资助国家：
美国
起止时间：
1983-01-01 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7379943
关键词：
ADD-1 protein Acute Acute Lung Injury Acyltransferase Adult Agonist Alveolar Asthma CCAAT-Enhancer-Binding Proteins Cell Differentiation process Data Enzymes Epithelial Cells Fatty Acids Future Gases Genes Glycerophospholipids Goals Human In Vitro Injury Lead Lecithin Ligands Lipids Lung Messenger RNA Mitogens Molecular Target Newborn Respiratory Distress Syndrome Palmitates Palmitoyl Coenzyme A Pathway interactions Pharmaceutical Preparations Phosphatidyl glycerol Phosphatidylglycerols Phospholipids Pneumonia Positioning Attribute Production Protein Isoforms Pulmonary Surfactants RRM1 gene RXR Rattus Regulation Respiratory distress Role SRE-1 binding protein Scheme Signal Pathway Signal Transduction Stearoyl-CoA Desaturase Techniques Type II Epithelial Receptor Cell alveolar epithelium alveolar type II cell base cell type disaturated lecithins drug development fatty acid biosynthesis improved in vivo keratinocyte growth factor lipid biosynthesis lipid metabolism novel response small airways disease small molecule surfactant therapeutic target transcription factor

项目摘要

Alveolar type II epithelial cells are critical for maintaining the gas exchange units of the lung. They produce pulmonary surfactant and restore the alveolar epithelium after injury. Keratinocyte growth factor (KGF) is a known mitogen for type II cells, stimulates type II cell differentiation in vitro, and protects the lung against a variety of injuries. In this proposal, we will examine the effects of KGF and other factors on the synthesis of fatty acids and phospholipids, which comprise the lipid components of pulmonary surfactant. KGF greatly stimulates overall phospholipid synthesis in vitro and specifically increases synthesis of phosphatidylcholine, disaturated phosphatidylcholine, and phosphatidylglycerol. In the first specific aim, we will determine the mechanism by which KGF stimulates fatty acid synthesis in rat type II cells. Based on our preliminary data, we believe the KGF stimulates fatty acid synthesis by activation of a coordinated group of transcription factors that include SREBP-1c and C/EBP isoforms. In addition, we will determine if ligands for LXRs, which increase SREBP-1c, increase surfactant production and lipogenic enzymes in vivo. A final portion of this specific aim will be to define the signaling pathways that increase lipogenic enzymes in response to KGF. Our focus will be on Akt, and its ability to regulate SREBP-1c and C/EBPa. The second specific aim will be to determine the regulation of surfactant phospholipid synthesis in primary cultures of human alveolar type II cells. The focus will be on SREBP-1c regulation of fatty acid synthesis in human type II cells. In the third specific aim we will characterize a novel acyltransferase that is selectively and highly expressed in type cells and whose mRNA level is increased 8-fold by KGF. We believe that this is a new glycerophospholipid acyltransferase that prefers lysoPC as the substrate and palmitoyl-CoA as the acyl donor. Specifically, the acyltransferase is important for the synthesis of dipalmitoylphosphatidylcholine (DPPC), the critical lipid in surfactant This proposal should greatly improve our understanding of the regulation of lipid metabolism in alveolar type II cells and should define potential regulatory targets for drug development in the future. This study will use adult human type II cells to determine mechanisms of surfactant production and identify molecular targets for the development of drugs for increasing surfactant production. In the future, such drugs could be used to treat acute lung injury, acute respiratory distress syndrome, respiratory distress of the newborn, severe pneumonias and diseases of small airways such as asthma.

肺泡 II 型上皮细胞对于维持肺的气体交换单位至关重要。他们生产肺表面活性物质，修复损伤后的肺泡上皮。角质形成细胞生长因子（KGF）是一种已知的 II 型细胞有丝分裂原，在体外刺激 II 型细胞分化，并保护肺部免受各种伤害。在本提案中，我们将研究 KGF 和其他因素对合成的影响脂肪酸和磷脂，构成肺表面活性物质的脂质成分。 KGF大大刺激体外磷脂的整体合成，特别是增加磷脂酰胆碱的合成，二饱和磷脂酰胆碱和磷脂酰甘油。在第一个具体目标中，我们将确定 KGF 刺激大鼠 II 型细胞脂肪酸合成的机制。根据我们的初步数据，我们相信 KGF 通过激活协调的转录组来刺激脂肪酸合成包括 SREBP-1c 和 C/EBP 亚型的因子。此外，我们将确定 LXR 的配体是否为增加SREBP-1c，增加体内表面活性剂的产生和脂肪生成酶。这一部分的最后一部分具体目标是确定响应 KGF 增加脂肪生成酶的信号通路。我们的重点将是 Akt 及其调节 SREBP-1c 和 C/EBPa 的能力。第二个具体目标是确定人 II 型肺泡原代培养物中表面活性剂磷脂合成的调节细胞。重点是 SREBP-1c 对人类 II 型细胞脂肪酸合成的调节。在第三个具体目标我们将表征一种新型酰基转移酶，该酶在类型中选择性和高度表达细胞的 mRNA 水平被 KGF 提高了 8 倍。我们相信这是一种新的甘油磷脂酰基转移酶更喜欢 lysoPC 作为底物和棕榈酰辅酶 A 作为酰基供体。具体来说，酰基转移酶对于二棕榈酰磷脂酰胆碱 (DPPC) 的合成很重要，DPPC 是细胞中的关键脂质。表面活性剂这个建议应该会大大提高我们对肺泡型脂质代谢调节的理解 II 细胞应该定义未来药物开发的潜在监管目标。本研究将使用成人 II 型细胞确定表面活性剂产生的机制并确定表面活性剂的分子靶标开发增加表面活性剂产量的药物。未来，此类药物可用于治疗急性肺损伤、急性呼吸窘迫综合征、新生儿呼吸窘迫、严重肺炎和小气道疾病，例如哮喘。