This grant studies the molecular interaction between lung and adipose tissue mediated by the adipocyte-derived hormone adiponectin. Adiponectin has been shown to act in murine lung to tonically inhibit endothelial cell activation and to limit injury originating from endothelial cell damage (e.g. hyperoxia). This proposal will utilize a broad range of genetic tools (e.g. adiponectin and adiponectin receptor deficient mice) and reagents (e.g. recombinant adiponectin protein, adenoviral vectors) to perform the first comprehensive examination of adiponectin's role in lung vascular homeostasis. Studies in Aim 1 will identify the oligomeric fractions and key structural domains mediating adiponectin's effects on lung endothelium and will elucidate the down-stream signaling pathways of adiponectin on lung endothelium. Studies in Aim 2 are designed to test the hypothesis that adiponectin mitigates lung injury to hyperoxia by activating anti- inflammatory and cyto-protective processes on lung endothelium. Finally, studies in Aim 3 will utilize in vitro and in vivo tools to identify the important adiponectin receptor mediating adiponectin's effects in lung. Taken together, studies in this grant will identify the molecular mechanisms by which APN regulates lung vascular processes in the hope of identifying new avenues of research in lung vascular biology and laying the foundation for the rational design of future clinical investigations examining APN in human lung disease.

Public Health Relevance

This grant introduces the novel concept that an adipocyte-derived hormone called adiponectin regulates homeostatic suppression of lung endothelium and mitigates lung injury originating from endothelial cell damage. Studies in this proposal aim to elucidate the molecular mechanisms mediating adiponectin's effects on murine lung endothelium in order to identify new strategies for developing novel therapies for prevention and treatment of human lung vascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL105490-04
Application #
8687725
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Xiao, Lei
Project Start
2011-08-01
Project End
2016-05-31
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Thomas Jefferson University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Shah, Dilip; Romero, Freddy; Guo, Zhi et al. (2017) Obesity-Induced Endoplasmic Reticulum Stress Causes Lung Endothelial Dysfunction and Promotes Acute Lung Injury. Am J Respir Cell Mol Biol 57:204-215
Fessler, Michael B; Summer, Ross S (2016) Surfactant Lipids at the Host-Environment Interface. Metabolic Sensors, Suppressors, and Effectors of Inflammatory Lung Disease. Am J Respir Cell Mol Biol 54:624-35
Shah, Dilip; Romero, Freddy; Zhu, Ying et al. (2015) C1q Deficiency Promotes Pulmonary Vascular Inflammation and Enhances the Susceptibility of the Lung Endothelium to Injury. J Biol Chem 290:29642-51
Shah, Dilip; Romero, Freddy; Duong, Michelle et al. (2015) Obesity-induced adipokine imbalance impairs mouse pulmonary vascular endothelial function and primes the lung for injury. Sci Rep 5:11362
Romero, Freddy; Shah, Dilip; Duong, Michelle et al. (2015) A pneumocyte-macrophage paracrine lipid axis drives the lung toward fibrosis. Am J Respir Cell Mol Biol 53:74-86
Kawwass, Jennifer F; Summer, Ross; Kallen, Caleb B (2015) Direct effects of leptin and adiponectin on peripheral reproductive tissues: a critical review. Mol Hum Reprod 21:617-32
Walkey, Allan J; Demissie, Serkalem; Shah, Dilip et al. (2014) Plasma Adiponectin, clinical factors, and patient outcomes during the acute respiratory distress syndrome. PLoS One 9:e108561
Romero, Freddy; Shah, Dilip; Duong, Michelle et al. (2014) Chronic alcohol ingestion in rats alters lung metabolism, promotes lipid accumulation, and impairs alveolar macrophage functions. Am J Respir Cell Mol Biol 51:840-9
Shah, Dilip; Romero, Freddy; Stafstrom, William et al. (2014) Extracellular ATP mediates the late phase of neutrophil recruitment to the lung in murine models of acute lung injury. Am J Physiol Lung Cell Mol Physiol 306:L152-61
Ding, Shi-Ying; Lee, Mi-Jeong; Summer, Ross et al. (2014) Pleiotropic effects of cavin-1 deficiency on lipid metabolism. J Biol Chem 289:8473-83

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