Pulmonary Surface Liquid Homeostasis

描述(申请人提供)：肺部表面的液体对维持肺部健康至关重要。PPG以CFTR、ENaC和细胞外嘌呤/嘌呤受体为研究重点，试图阐明1)在局部水平调节肺表面液体和2)整合呼吸道和肺泡表面液体生理的分子机制。为了实现这些目标，PPG需要四个项目。项目I(CFTR功能和功能障碍中的动力学和热稳定性，J.R.Riordan，Ph.D.，P.L.)建议研究野生型CFTR的温度稳定性的机制，以及重要的是？F508CFTR在生理温度下的温度不稳定性。项目II(CFTR-ENaC在人类呼吸道上皮中的调节和结构相互作用，M.J.Stutts，Ph.D.，P.L.)建议在结构、功能和调控水平上研究CFTR和ENaC在呼吸道上皮细胞中调控关系的分子基础。项目III(肺泡上皮中CFTR-ENaC相互作用的嘌呤能控制，R.C.Boucher，M.D.，P.L.)建议研究嘌呤受体对肺泡表面CFTR-ENaC相互关系的调节作用，重点研究在控制肺泡液体流动方向中，嘌呤受体抑制ENaC的优势。项目四(肺内核苷酸释放的机制和后果，E.R.Lazarowski，Ph.D.，P.L.)将研究呼吸道上皮细胞核苷酸释放的机制、调节和后果，调查水泡性和传导性释放途径在健康中的相对作用及其在主要呼吸道疾病发病机制中的作用。PPG项目得到三个核心的支持：一个行政核心；一个细胞培养核心；以及一个分子生物学核心。通过聚焦于三个主要主题，即CFTR、ENaC和嘌呤受体配体-受体相互作用，从分子到系统生物学长度尺度，PPG建议1)对局部肺表面液体稳态离子通道数量/活性的调节产生详细的分子理解，2)将这些活动整合到整个肺表面，为理解正常生理、疾病发病机制和设计针对人类主要肺部疾病的新疗法提供框架。

DESCRIPTION (provided by applicant): The liquids that line the surface of the lung are critical for the maintenance of lung health. Focusing on CFTR, ENaC, and extracellular purines/purinoceptors, the PPG proposes to elucidate the molecular mechanisms that 1) regulate pulmonary surface liquid at local levels and 2) integrate airway and alveolar pulmonary surface liquid physiologies. To accomplish these goals, the PPG requires four Projects. Project I (Dynamics and Thermal Stability in CFTR Function and Dysfunction, J. R. Riordan, Ph.D., P.l.) proposes to study the mechanisms that confer temperature stability to wild-type CFTR, and, importantly, the temperature instability at physiologic temperatures of ?F508 CFTR. Project II (CFTR-ENaC Regulatory and Structural Interactions in Human Airway Epithelia, M.J. Stutts, Ph.D., P.l.) proposes to study the molecular basis for the regulatory relationship between CFTR and ENaC in airway epithelia at the structural, functional, and the regulatory levels. Project III (Purinergic Control of CFTR-ENaC Interactions in Alveolar Epithelia, R.C. Boucher, M.D., P.l.) proposes to study purinoceptor regulation of the CFTR-ENaC interrelationship on alveolar surfaces, focusing on the dominance of purinoceptor inhibition of ENaC in controlling the direction of alveolar liquid flow. Project IV (Mechanisms and Consequences of Nucleotide Release in the Lung, E. R. Lazarowski, Ph.D., P.l.) will investigate the mechanisms, regulation, and consequences of nucleotide release in airway epithelia, investigating the relative roles of vesicular vs. conductive release paths in health and their contribution to the pathogenesis of major airways diseases. The PPG Projects are supported by three Cores: an Administrative Core; a Cell Culture Core; and a Molecular Biology Core. By focusing on three major themes, i.e., CFTR, ENaC, and purinoceptor ligand-receptor interactions, from molecular to systems biology length scales, the PPG proposes to 1) generate a detailed molecular understanding of the regulation of Ion channel number/activity for local pulmonary surface liquid homeostasis and 2) integrate these activities over the entire surface of the lung to provide the framework for understanding normal physiology, disease pathogenesis, and design of novel therapies for major human lung diseases.