Pulmonary Surface Liquid Homeostasis

描述（由申请人提供）：排列在肺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/嘌呤受体为重点，提出阐明1)在局部水平调节肺表面液和2)整合气道和肺泡肺表面液生理的分子机制。为了实现这些目标，PPG需要四个项目。项目一（CFTR功能和功能障碍的动力学和热稳定性，J. R. Riordan, Ph.D.， P.l.）提出研究野生型CFTR赋予温度稳定性的机制，更重要的是，在生理温度下的温度不稳定性。F508雌性生殖道。Project II （CFTR-ENaC Regulatory and Structural Interactions in Human Airway epithelial， M.J. Stutts, Ph.D.， P.l.）从结构、功能和调控水平研究CFTR和ENaC在气道上皮中的调控关系的分子基础。Project III （Purinergic Control of CFTR-ENaC Interactions in Alveolar epithelial， R.C. Boucher, m.d., p.l.）提出研究purinepreceptor对肺泡表面CFTR-ENaC相互作用的调控，重点研究purinepreceptor对ENaC的抑制在控制肺泡液体流动方向中的主导作用。项目四（肺内核苷酸释放的机制和后果，E. R. Lazarowski, Ph.D.， P.l.）将研究气道上皮内核苷酸释放的机制、调控和后果，研究水泡和导电释放途径在健康中的相对作用及其对主要气道疾病发病机制的贡献。PPG项目由三个核心提供支持：行政核心；细胞培养芯；和分子生物学核心。通过关注CFTR、ENaC和嘌呤受体配体-受体相互作用这三个主要主题，从分子到系统生物学的长度尺度，PPG提出：1)对局部肺表面液体稳态中离子通道数量/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，为理解正常生理学、疾病发病机制、以及设计针对人类主要肺部疾病的新疗法。

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.