Adult respiratory distress syndrome (ARDS) is a devastating syndrome responsible for significant morbidity and mortality in our intensive care units. The pathogenesis of ARDS is still poorly understood and therapeutic options remain limited despite the recent progress in protective low tidal volume ventilatory strategies. Hyperoxia-induced lung injury is a well established model which mimics human ARDS and has been used extensively by investigators during the past several decades to better understand the pathogenesis of ARDS. A novel class of molecules named """"""""CCN"""""""" family were reported in the 1990's, having diverse biological functions including wound healing, angiogenesis, fibrogenesis, tumorigenesis and lung development. The CCN family includes six 30-40 kDa proteins that are extremely cysteine-rich and was named after its first three members (cysteine-rich 61 (Cyr61), connective tissue growth factor (CTGF) and nephroblastoma overexpressed (NOV). Cyr61, one of the CCN proteins, was identified as a TGF-n inducible immediate early gene and demonstrated to be involved in cell proliferation, adhesion and early response to stress. Despite the accumulating evidence that Cyr61 is critical in angiogenesis, wound healing and repair in other tissue organs, Cyr61 has not been extensively studied in lung cells or in vivo models of lung diseases, especially its potential roles in acute lung injury. Our laboratory has focused in learning more about this intriguing molecule, potentially a novel molecular target in acute lung injury. To this end, we have obtained provocative preliminary data that Cyr61 is highly expressed in lung tissues and in various lung cells after hyperoxia. Our recent preliminary data also demonstrate that Cyr61 protects against hyperoxia-induced lung epithelial cell death in vitro. This cytoprotective effect of Cyr61 might function via Akt pathways. Based on our Preliminary Studies, we hypothesize that Cyr61 expression is regulated by hyperoxia transcriptionally and confers cytoprotection against hyperoxia via Akt related pathways. We further hypothesize that Cyr61 protects hyperoxia-induced acute lung injury in vivo. We will test our hypothesis by addressing the following specific aims:
Specific Aims I : To determine the regulation of Cyr61 expression after hyperoxia Specific Aims II: To determine the mechanism(s) by which Cyr61 protects against hyperoxia-induced cell death and injury in vitro Specific Aims III: To determine the mechanism(s) by which Cyr61 protects against hyperoxia-induced lung injury in vivo

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL085601-04
Application #
7664946
Study Section
Special Emphasis Panel (ZHL1-CSR-O (M1))
Program Officer
Colombini-Hatch, Sandra
Project Start
2006-08-01
Project End
2009-09-11
Budget Start
2009-08-01
Budget End
2009-09-11
Support Year
4
Fiscal Year
2009
Total Cost
$126,225
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Liang, Xiaoliang; Wei, Shu-Quan; Lee, Seon-Jin et al. (2013) p62 sequestosome 1/light chain 3b complex confers cytoprotection on lung epithelial cells after hyperoxia. Am J Respir Cell Mol Biol 48:489-96
Jin, Yang; Lee, Seon-Jin; Minshall, Richard D et al. (2011) Caveolin-1: a critical regulator of lung injury. Am J Physiol Lung Cell Mol Physiol 300:L151-60
Lee, Seon-Jin; Smith, Akaya; Guo, Lanping et al. (2011) Autophagic protein LC3B confers resistance against hypoxia-induced pulmonary hypertension. Am J Respir Crit Care Med 183:649-58
Chen, Zhi-Hua; Lam, Hilaire C; Jin, Yang et al. (2010) Autophagy protein microtubule-associated protein 1 light chain-3B (LC3B) activates extrinsic apoptosis during cigarette smoke-induced emphysema. Proc Natl Acad Sci U S A 107:18880-5
Zhang, Meng; Lin, Ling; Lee, Seon-Jin et al. (2009) Deletion of caveolin-1 protects hyperoxia-induced apoptosis via survivin-mediated pathways. Am J Physiol Lung Cell Mol Physiol 297:L945-53
Jin, Yang; Kim, Hong Pyo; Cao, Jiaofei et al. (2009) Caveolin-1 regulates the secretion and cytoprotection of Cyr61 in hyperoxic cell death. FASEB J 23:341-50
Jin, Yang; Kim, Hong Pyo; Chi, Minli et al. (2008) Deletion of caveolin-1 protects against oxidative lung injury via up-regulation of heme oxygenase-1. Am J Respir Cell Mol Biol 39:171-9