Alveolar epithelium serves as a barrier function for a selective transport of ions. Fluid secretion in the fluid-filled fetal lungs is driven by active secretion of Cl- and is critical for fetal lung development. On the other hand, Na+-driven fluid absorption in the air-filled adult lung is dominated to maintain a """"""""dry"""""""" lung. However, even in the adult lungs, Cl- -driven fluid secretion is still needed to maintain a thin layer of liquid, covering alveolar air surface, which is essential for gas exchange. Na+ transport in the lung has been extensively studied in the past. However, our knowledge of Cl- channels in both fetal and adult lungs is very limited. The molecular identity of Cl- channels responsible for Cl- secretion in the fetal and adult distal lungs remains to be identified. Our long-term goal is to elucidate the roles of ion channels in fluid homeostasis in the fetal and adult lungs and underlying cellular and molecular mechanisms. Gamma-aminobutyric acid (GABA) receptors are the ligand-gated Cl- channels that mediate rapid inhibitory transmissions in the central nervous system. Our preliminary studies have indicated that GABA receptors may participate in fluid secretion in the fetal lung and alveolar fluid clearance in the adult lung. In the current proposal, we will determine physiological and functional significance of GABA receptors in the fetal and adult lungs and study their regulatory mechanisms using molecular, cellular, and physiological approaches at all levels from gene to whole animal. Our central hypothesis in the proposal is that GABA receptors secrete Cl- to drive fluid secretion in the fetal and adult lungs and are essential for fetal lung development and maintaining fluid homeostasis in the adult lung.
Three specific aims are proposed to test the hypothesis.
Aim I will evaluate the role of GABA receptors in Cl- and fluid secretions and fetal lung development.
Aim II will examine the role of GABA receptors in fluid homeostasis in the adult normal and injured lungs.
Aim III will determine the post-translational regulation of GABA receptors by protein phosphorylation. An understanding of the mechanisms of fluid transport in the lung will provide valuable insights and directions toward therapeutic intervention in fetal lung diseases and the resolution of pulmonary edema. ? ?
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