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：
7586230
负责人：
ROBERT James MASON
金额：
$ 35.78万
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 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7586230
关键词：
ADD-1 protein Acute Acute Lung Injury Acyltransferase Adult Adult Respiratory Distress Syndrome 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 Infant 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.

牙槽II型上皮细胞对于维持肺的气体交换单位至关重要。他们产生肺表面活性剂并在受伤后恢复肺泡上皮。角质形成细胞生长因子（kgf）是已知用于II型细胞的有丝分裂原，刺激体外II型细胞分化，并保护肺部免受A 各种伤害。在此提案中，我们将研究KGF和其他因素对合成的影响脂肪酸和磷脂，包括肺表面活性剂的脂质成分。 kgf很大刺激体外刺激总体磷脂合成，特别增加了磷脂酰胆碱的合成，磷脂酰胆碱和磷脂酰甘油醇的饱和。在第一个特定目标中，我们将确定 KGF刺激大鼠II型细胞中脂肪酸合成的机制。根据我们的初步数据我们认为KGF通过激活一组转录刺激脂肪酸合成包括SREBP-1C和C/EBP同工型在内的因素。此外，我们将确定LXR的配体是否在体内增加SREBP-1C，增加表面活性剂的产生和脂肪生物。最后一部分具体目的是定义响应KGF的脂肪生物酶的信号传导途径。我们的重点将放在AKT及其调节SREBP-1C和C/EBPA的能力上。第二个特定目标将是确定在人类牙槽II型原代培养物中表面活性剂磷脂合成的调节细胞。重点将放在人类II型细胞中脂肪酸合成的SREBP-1C调节。在第三具体目的，我们将表征一种新型的酰基转移酶细胞且其mRNA水平通过kgf升高了8倍。我们认为这是一种新的甘油磷脂酰基转移酶偏爱lysopc作为底物，而棕榈酰-COA作为酰基供体。具体来说，酰基转移酶对于二氨酰磷脂酰胆碱（DPPC）的合成至关重要，这是临界脂质表面活性剂该提案应大大提高我们对肺泡类型脂质代谢调节的理解 II细胞并应定义未来药物开发的潜在调节靶标。这项研究将使用成人人类II型细胞确定表面活性剂的机理并确定分子靶标的用于增加表面活性剂产生的药物的开发。将来，这种药物可以用来治疗急性肺损伤，急性呼吸窘迫综合征，新生儿的呼吸窘迫，严重小型气道（例如哮喘）的肺炎和疾病。