Aquaporin 5 (AQP5) in Lung Fluid Homeostasis

水通道蛋白 5 (AQP5) 在肺液稳态中的作用

• 批准号: 6804923
• 负责人: CARISSA M KRANE
• 金额: $ 22.13万
• 依托单位: UNIVERSITY OF DAYTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6804923
• 关键词: HeLa cells; asthma; biological fluid transport; body fluids; chemical cleavage; crosslink; disease /disorder model; functional /structural genomics; gel mobility shift assay; gene expression; gene expression profiling; gene mutation; genetically modified animals; homeostasis; human genetic material tag; human tissue; laboratory mouse; lung; messenger RNA; microarray technology; neoplastic cell culture for noncancer research; posttranscriptional RNA processing; protein structure function; single nucleotide polymorphism; water channel

DESCRIPTION (provided by applicant): The maintenance of fluid homeostasis is a critical parameter in establishing and maintaining normal physiology. Control of membrane water flux through membrane water pores (aquaporins; AQP) is essential for the ability of an organism to adapt to changing fluid environments. The function and regulation of individual AQP proteins is central to many physiological pathways including salivary secretion, urinary concentration, sweat production, and lung mechanics. Of specific interest to the study of lung mechanics is a member of this family, Aquaporin 5 (AQP5), and its functional role in mediating fluid regulatory mechanisms in the lung. Recent work has shown that AQP5 function is crucial in modulating bronchoconstrictive responses. Mice deficient in AQP5 are hyperresponsive to cholinergic-stimulated bronchoconstriction (narrowing of the airways), a clinical feature of asthma. Asthma is a common, complex genetic disease caused by a combination of inherited and environmental factors. Asthma affects nearly 15 million Americans, one third of them children. It is likely that not just one or a few, but rather several genes interact together, and with the environment, to elicit the hyperconstrictive airway response characteristic of clinical asthma. We do not currently understand how AQP5 functions normally in the lung, and why disruptions in this water channel results in an asthma-like pathophysiological state in mice. The proposed experiments use a combination of physiological, functional genomic and biochemical approaches to identify the pathways in which AQP5 is involved in maintaining proper lung fluid mechanics. Specifically, in vitro biochemical RNA processing assays will be used to determine the effects of AQP5 gene mutation on AQP5 gene expression. An AQP5-deficient mouse model of asthma will be used to identify the mechanistic genomic effects of AQP5 deficiency in the lung. This combinatorial approach will provide valuable information for the identification of new mechanistic pathways critical for the development of novel drug targets for the treatment of asthma.

描述（由申请人提供）：液体稳态的维持是建立和维持正常生理学的关键参数。控制通过膜水孔（水通道蛋白; AQP）的膜水通量对于生物体适应变化的流体环境的能力至关重要。单个AQP蛋白的功能和调节是许多生理途径的中心，包括唾液分泌、尿浓缩、汗液产生和肺力学。特别感兴趣的肺力学的研究是这个家庭的成员，水通道蛋白5（AQP 5），其功能作用介导的液体调节机制在肺。最近的研究表明，AQP 5的功能是至关重要的，在调节支气管收缩反应。缺乏AQP 5的小鼠对胆碱能刺激的支气管收缩（气道变窄）反应过度，这是哮喘的一个临床特征。哮喘是一种常见的、复杂的遗传性疾病，由遗传和环境因素共同引起。哮喘影响着近1500万美国人，其中三分之一是儿童。很可能不是一个或几个，而是几个基因一起相互作用，并与环境，引起临床哮喘的气道过度收缩反应特征。我们目前还不了解AQP 5在肺中的正常功能，以及为什么这种水通道的中断会导致小鼠出现哮喘样病理生理状态。拟议的实验使用生理，功能基因组和生化方法的组合，以确定AQP 5参与维持适当的肺流体力学的途径。具体而言，将使用体外生物化学RNA加工测定来确定AQP 5基因突变对AQP 5基因表达的影响。将使用AQP 5缺陷型哮喘小鼠模型来鉴定肺中AQP 5缺陷的机制基因组效应。这种组合的方法将提供有价值的信息，为识别新的机制的途径，为开发新的药物靶点治疗哮喘的关键。

项目成果

Altered regulation of aquaporin gene expression in allergen and IL-13-induced mouse models of asthma.

• DOI: 10.1016/j.cyto.2008.12.018
• 发表时间: 2009-04
• 期刊: CYTOKINE
• 影响因子: 3.8
• 作者: Krane, Carissa M.;Deng, Bijia;Mutyam, Venkateshwar;McDonald, Casey A.;Pazdziorko, Stephen;Mason, Lawrence;Goldman, Samuel;Kasaian, Marion;Chaudhary, Divya;Williams, Cara;Ho, Melisa W. Y.
• 通讯作者: Ho, Melisa W. Y.