Aquaporin 5 (AQP5) in Lung Fluid Homeostasis

描述（由申请人提供）：维持体液稳态是建立和维持正常生理的关键参数。通过膜水孔（水通道蛋白；AQP）控制膜水通量对生物体适应不断变化的流体环境的能力至关重要。单个AQP蛋白的功能和调控是许多生理途径的核心，包括唾液分泌、尿浓度、汗液产生和肺力学。对肺力学的研究特别感兴趣的是这个家族的成员，水通道蛋白5 (AQP5)，及其在调节肺液体调节机制中的功能作用。最近的研究表明，AQP5在调节支气管收缩反应中起着至关重要的作用。缺乏AQP5的小鼠对胆碱能刺激的支气管收缩（气道狭窄）反应过度，这是哮喘的临床特征。哮喘是一种常见的、复杂的遗传疾病，由遗传和环境因素共同引起。近1500万美国人患有哮喘，其中三分之一是儿童。很可能不仅仅是一个或几个基因，而是几个基因共同作用，并与环境相互作用，引起临床哮喘的气道过度收缩反应特征。我们目前还不清楚AQP5如何在肺中正常发挥作用，以及为什么这种水渠的破坏会导致小鼠出现类似哮喘的病理生理状态。本实验采用生理学、功能基因组学和生化方法相结合的方法来确定AQP5参与维持适当肺流体力学的途径。具体而言，我们将采用体外生化RNA处理试验来确定AQP5基因突变对AQP5基因表达的影响。我们将使用AQP5缺失小鼠哮喘模型来确定AQP5缺失在肺中的机制基因组效应。这种组合方法将为鉴定新的机制途径提供有价值的信息，这对于开发治疗哮喘的新药物靶点至关重要。

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.