Regulation of CFTR by adenosine, A2 receptors, and PLA2

腺苷、A2 受体和 PLA2 对 CFTR 的调节

• 批准号: 6745957
• 负责人: John Paul Clancy
• 金额: $ 24.87万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-03 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6745957
• 关键词: adenosine; arachidonate; chloride channels; cystic fibrosis; electrophysiology; human subject; immunocytochemistry; inflammation; ion transport; laboratory mouse; leukocyte activation /transformation; membrane permeability; patient oriented research; phospholipase A2; potentiometry; purinergic receptor; receptor coupling; receptor expression; respiratory epithelium; secretion; tissue /cell culture

DESCRIPTION(adapted from applicant's abstract): Cystic fibrosis is characterized by defective epithelial ion transport in the airways, bacterial infection, and intense, leukocyte-dominated inflammation. Together, these processes contribute to the progressive airway destruction characteristic of the disease. Mutations in CFTR initiate this cascade, creating an abnormal airway surface liquid microenvironment. While CF-specific abnormalities in ion transport and inflammation have been described and are currently under intense investigation, the factors within the airway microenvironment that modulate both fundamental aspects of CF airway disease are not clearly identified. Adenosine is an endogenous autocoid that is an attractive candidate molecule, activating C1- secretion across airway and other CFTR-expressing epithelia, and modulating many important aspects of leukocyte (neutrophil and macrophage) function. Evidence also suggests that both airway epithelia and inflammatory cells export adenosine nucleotides which are metabolized in the extracellular environment to adenosine. Cellular signaling is primarily through adenosine receptors, including A2 receptors. This proposal is intended to characterize how the inflammatory regulator adenosine, through A2 receptors, activates CFTR. Our preliminary results suggest that A2 receptors activate CFTR through phospholipase A2 (PLA2) and arachidonic acid. This signaling pathway represents a novel, previously undescribed mechanism to modulate CFTR activity. The studies outlined in this proposal will: (1) characterize A2 receptor activation of CFTR-dependent Cl transport in living cells and across airway epithelia in vivo, (2) determine whether adenosine is a predominant nucleotide in the airway microenvironment, and (3) help to develop and test strategies to improve the detection of wildtype CFTR activity, and to improve the function of mutant CFTRs in vitro and in vivo. Adenosine signaling provides a new framework in which to consider the interactions between the epithelia and immune system within the airway microenvironment, helping to bridge the gap between inflammation, CFTR, and Cl- secretion. The experiments outlined also identify a new way to regulate CFTR, and therefore may help define new therapeutic targets in the disease.

描述（改编自申请人的摘要）：囊性纤维化是 其特征在于气道中上皮细胞离子转运缺陷， 感染以及以白细胞为主的强烈炎症。所有这些 这些过程有助于进行性气道破坏， 这种疾病CFTR的突变启动了这一级联反应， 气道表面液体微环境。虽然CF特异性离子异常 运输和炎症已经被描述，目前正在激烈的 研究中，气道微环境中的因素， CF气道疾病的两个基本方面都没有被清楚地识别。 腺苷是一种内源性autocoid，是一种有吸引力的候选分子， 激活跨气道和其它表达CFTR的上皮细胞的C1分泌，和 调节白细胞（中性粒细胞和巨噬细胞）的许多重要方面 功能证据还表明，气道上皮细胞和炎性细胞 细胞输出在细胞外代谢的腺苷核苷酸 环境对腺苷。细胞信号主要通过腺苷 包括A2受体。该提案旨在描述 炎症调节剂腺苷如何通过A2受体激活CFTR。 我们的初步结果表明，A2受体激活CFTR通过 磷脂酶A2（PLA 2）和花生四烯酸。这个信号通路代表了 一种新的，以前未描述的机制来调节CFTR活性。的 本提案中概述的研究将：（1）表征A2受体活化 CFTR依赖的氯离子转运在活细胞和气道上皮细胞中的作用 体内，（2）确定腺苷是否是气道中的主要核苷酸 微环境，以及（3）帮助开发和测试策略，以改善 检测野生型CFTR活性，并改善突变体的功能 CFTR在体外和体内。腺苷信号转导提供了一个新的框架， 考虑上皮细胞和免疫系统之间的相互作用 在气道微环境中，有助于弥合气道微环境之间的差距， 炎症、CFTR和Cl-分泌。概述的实验还确定了一个 一种调节CFTR的新方法，因此可能有助于确定新的治疗靶点 在疾病中。