Investigation of how activation of AMP activated protein kinase (AMPK) inhibits Na+ transport across H441 lung epithelial cells.

研究 AMP 激活蛋白激酶 (AMPK) 的激活如何抑制 Na 通过 H441 肺上皮细胞的转运。

• 批准号: BB/E013597/1
• 负责人: Deborah Baines
• 金额: $ 34.76万
• 依托单位: St George's, University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2007
• 资助国家: 英国
• 起止时间: 2007 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FE013597%2F1
• 关键词: Investigation; how; activation; AMP; activated

The airways of the lung are lined with a thin layer of fluid that is important in preventing infection and damage from inhaled agents. The volume of this fluid layer is controlled by the transport of sodium and chloride across the cells that line the surface of the airways through selective channels and pumps. Increased transport of sodium out of the airway is linked with dehydration of the fluid layer and is a contributary factor to the disease, Cystic Fibrosis. Conversely, a decrease in sodium transport is associated with fluid accumulation in the airways as in respiratory distress syndrome of the newborn and high altitude pulmonary oedema. We have recently discovered that activation of a molecule that senses low cellular energy levels (adenosine monophosphate-activated protein kinase (AMPK), decreases sodium transport across the lung epithelial cell. AMPK may therefore have a significant regulatory role in these diseases. How AMPK decreases sodium transport is unknown but it appears to reduce the amount of sodium entering the cell via the amiloride-sensitive sodium channel (ENaC) and the amount of sodium that is extruded from the cell via the Na+K+ATPase pump. It is the purpose of this project to investigate if activation of AMPK decreases sodium transport and the activity of ENaC and Na+K+ATPase by regulating the abundance of these proteins in the cell membrane. We will do this by using a combination of functional and molecular approaches in human H441 lung epithelial cells in vitro. Identifying the cellular mechanism by which this molecule regulates sodium transport is a critical first step in elucidating how it could regulate Na+ transport in vivo. This will help us develop more appropriate strategies for future research and the development of treatments for lung diseases which exhibit dissordered fluid volume.

肺的气道内衬有一层薄薄的液体，这对于防止吸入剂引起的感染和损伤很重要。该液体层的体积由钠和氯化物通过选择性通道和泵穿过气道表面的细胞的运输来控制。增加的钠转运出气道与液体层脱水有关，并且是囊性纤维化疾病的促成因素。相反，钠转运的减少与气道中的液体积聚有关，如新生儿呼吸窘迫综合征和高原肺水肿。我们最近发现，激活一种能感知低细胞能量水平的分子（腺苷一磷酸激活蛋白激酶（AMPK）），会降低肺上皮细胞的钠转运。因此AMPK可能在这些疾病中具有重要的调节作用。AMPK如何减少钠转运尚不清楚，但它似乎减少了通过阿米洛利敏感性钠通道（ENaC）进入细胞的钠量和通过Na+K+ ATP酶泵从细胞中排出的钠量。本研究的目的是研究AMPK的激活是否通过调节细胞膜上这些蛋白的丰度来降低钠转运以及ENaC和Na+K+ ATP酶的活性。我们将通过在体外人H441肺上皮细胞中使用功能和分子方法的组合来实现这一点。确定这种分子调节钠转运的细胞机制是阐明它如何调节体内Na+转运的关键第一步。这将有助于我们为未来的研究和发展肺部疾病的治疗方法，表现出紊乱的液体体积开发更合适的策略。

项目成果

The phosphorylation of endogenous Nedd4-2 In Na(+)-absorbing human airway epithelial cells.

• DOI: 10.1016/j.ejphar.2014.03.005
• 发表时间: 2014-06-05
• 期刊: EUROPEAN JOURNAL OF PHARMACOLOGY
• 影响因子: 5
• 作者: Ismail, Noor A. S.;Baines, Deborah L.;Wilson, Stuart M.
• 通讯作者: Wilson, Stuart M.

Kinases as targets for ENaC regulation.

• DOI: 10.2174/18744672112059990028
• 发表时间: 2013-02
• 期刊: Current molecular pharmacology
• 影响因子: 2.7
• 作者: D. Baines

Lipopolysaccharide modifies amiloride-sensitive Na+ transport processes across human airway cells: role of mitogen-activated protein kinases ERK 1/2 and 5.

脂多糖修饰了跨人类气道细胞的艾米洛德敏感的Na+转运过程：有丝分裂原激活的蛋白激酶ERK 1/2和5的作用。

• DOI: 10.1007/s00424-009-0717-4
• 发表时间: 2010-02
• 期刊: PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
• 影响因子: 4.5
• 作者: Baines, D. L.;Albert, A. P.;Hazell, M. J.;Gambling, L.;Woollhead, A. M.;Dockrell, M. E. C.
• 通讯作者: Dockrell, M. E. C.