Defining a mechanism for altered PUFA metabolism in cystic fibrosis

定义囊性纤维化中 PUFA 代谢改变的机制

• 批准号: 8595012
• 负责人: Obinna Umunakwe
• 金额: $ 2.69万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8595012
• 关键词: 5' -AMP-activated protein kinase; AMP-activated protein kinase kinase; Affect; Age-Years; Arachidonic Acids; Biological Models; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium; Calcium/calmodulin-dependent protein kinase; Cell physiology; Cells; Cellular Stress; Characteristics; Chronic; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Development; Disease; Docosahexaenoic Acids; Enzymes; Epithelial Cells; Exhibits; Fatty Acid Desaturases; Fatty Acids; Infection; Inflammation; Lead; Life; Life Expectancy; Link; Linoleic Acids; Lipids; Lung diseases; Malonyl Coenzyme A; Mammalian Cell; Mediating; Membrane; Metabolic; Morbidity - disease rate; Mutation; Pathogenesis; Pathologic; Patients; Phenotype; Phosphorylation; Phosphotransferases; Play; Polyunsaturated Fatty Acids; Proteins; RNA Interference; Reaction; Recurrence; Role; STK11 gene; Signal Transduction; Supplementation; Testing; Therapeutic; Tissues; United States; apical membrane; base; cystic fibrosis mouse; cystic fibrosis patients; desaturase; fatty acid metabolism; insight; lipid metabolism; mRNA Expression; mortality; mouse model; novel therapeutics; oxidation; public health relevance; response

DESCRIPTION (provided by applicant): Cystic fibrosis (CF) is an autosomal recessive disease caused by absence of functional cystic fibrosis Tran's membrane conductance regulator (CFTR) protein in epithelial cells. The major cause of morbidity and mortality in patients with CF is chronic pulmonary disease characterized by persistent inflammation and recurrent infections. CF patients have characteristic alterations in polyunsaturated fatty acid (PUFA) composition in CFTR-expressing tissues, including increased arachidonic acid, and reduced linoleic acid and docosahexaenoic acid (DHA). These alterations are a consequence of altered PUFA metabolism in CF, including increased expression and activity of ?6-desaturase (D6D). In a CF mouse model, DHA supplementation diminishes the CF phenotype, suggesting that these alterations play an important role in CF pathogenesis. However, the mechanism by which CFTR mutations lead to alterations in PUFA metabolism is unclear. Preliminary data suggests that increased AMP-activated protein kinase (AMPK) activity in CF plays a role. The proposed study seeks to test the hypothesis that PUFA metabolic alterations in CF are a consequence of increased AMPK activity through completion of the following aims: (1) elucidate the mechanism by which AMPK activity is increased in CF, and (2) determine the impact of AMPK activity on PUFA metabolism in CF. Completion of the proposed study will provide insight into the mechanism linking CF and PUFA metabolism. Better understanding of this mechanism will contribute to the development of potential lipid-based therapies for CF patients.

描述（由申请人提供）：囊性纤维化（CF）是一种常染色体隐性遗传疾病，由上皮细胞中功能性囊性纤维化Tran膜电导调节蛋白（CFTR）缺失引起。 CF 患者发病和死亡的主要原因是慢性肺部疾病，其特征是持续炎症和反复感染。 CF 患者表达 CFTR 的组织中多不饱和脂肪酸 (PUFA) 组成发生特征性改变，包括花生四烯酸增加、亚油酸和二十二碳六烯酸 (DHA) 减少。这些改变是 CF 中 PUFA 代谢改变的结果，包括 β6-去饱和酶 (D6D) 的表达和活性增加。在 CF 小鼠模型中，补充 DHA 可减少 CF 表型，表明这些改变在 CF 发病机制中发挥重要作用。然而，CFTR 突变导致 PUFA 代谢改变的机制尚不清楚。初步数据表明，CF 中 AMP 激活蛋白激酶 (AMPK) 活性的增加发挥了作用。拟议的研究旨在通过完成以下目标来检验 CF 中 PUFA 代谢变化是 AMPK 活性增加的结果这一假设：(1) 阐明 CF 中 AMPK 活性增加的机制，以及 (2) 确定影响CF 中 AMPK 活性对 PUFA 代谢的影响。完成拟议的研究将有助于深入了解 CF 和 PUFA 代谢之间的联系机制。更好地了解这一机制将有助于开发针对 CF 患者的潜在脂质疗法。