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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL083188-01
Application #
7025297
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Denholm, Elizabeth M
Project Start
2006-07-01
Project End
2010-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
1
Fiscal Year
2006
Total Cost
$366,000
Indirect Cost
Name
Oklahoma State University Stillwater
Department
Physiology
Type
Schools of Veterinary Medicine
DUNS #
049987720
City
Stillwater
State
OK
Country
United States
Zip Code
74078
Guo, Yujie; Mishra, Amarjit; Howland, Emily et al. (2015) Platelet-derived Wnt antagonist Dickkopf-1 is implicated in ICAM-1/VCAM-1-mediated neutrophilic acute lung inflammation. Blood 126:2220-9
Guo, Y; Mishra, A; Weng, T et al. (2014) Wnt3a mitigates acute lung injury by reducing P2X7 receptor-mediated alveolar epithelial type I cell death. Cell Death Dis 5:e1286
Kang, Kang; Peng, Xiao; Zhang, Xiaoying et al. (2013) MicroRNA-124 suppresses the transactivation of nuclear factor of activated T cells by targeting multiple genes and inhibits the proliferation of pulmonary artery smooth muscle cells. J Biol Chem 288:25414-27
Chintagari, Narendranath Reddy; Liu, Lin (2012) GABA receptor ameliorates ventilator-induced lung injury in rats by improving alveolar fluid clearance. Crit Care 16:R55
Bhaskaran, Manoj; Xi, Dong; Wang, Yang et al. (2012) Identification of microRNAs changed in the neonatal lungs in response to hyperoxia exposure. Physiol Genomics 44:970-80
Mishra, Amarjit; Chintagari, Narendranath Reddy; Guo, Yujie et al. (2011) Purinergic P2X7 receptor regulates lung surfactant secretion in a paracrine manner. J Cell Sci 124:657-68
Zhang, Honghao; Mishra, Amarjit; Chintagari, Narendranath Reddy et al. (2010) Micro-RNA-375 inhibits lung surfactant secretion by altering cytoskeleton reorganization. IUBMB Life 62:78-83
Chintagari, Narendranath Reddy; Mishra, Amarjit; Su, Lijing et al. (2010) Vacuolar ATPase regulates surfactant secretion in rat alveolar type II cells by modulating lamellar body calcium. PLoS One 5:e9228
Weng, Tingting; Liu, Lin (2010) The role of pleiotrophin and beta-catenin in fetal lung development. Respir Res 11:80
Chintagari, Narendranath Reddy; Jin, Nili; Gao, Li et al. (2010) Role of GABA receptors in fetal lung development in rats. PLoS One 5:e14171

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