Prematurely born human infants often develop chronic lung disease (CLD), in which inflammation is a key upstream event. The ability to overcome and resolve the adverse effects of lung inflammation may in fact determine whether an infant will go on to develop CLD or not. The mechanisms that negatively regulate and terminate inflammation, both in the lung and elsewhere, are poorly understood. Upon injection with LPS, a bacterial endotoxin, mice lacking Bcr and Abr die of sepsis with lung injury because they are unable to down regulate and resolve an episode of acute inflammation. These two related proteins negatively regulate a small GTPase, Rac. Macrophages Iacking A br a nd B cr contain elevated Ievels o f active R ac. Active R ac stimulates multiple functions of inflammatory cells including phagocytosis, motility and reactive oxygen species production. Based on our preliminary data, we hypothesize that Bcr and Abr negatively regulate inflammation in the lung through their action on Rac. Our studies are aimed at deciphering the tempo-spatial events (cell types, recruitment kinetics, interactions, cytokines) that lead to increased lung injury in mice lacking Abr and Bcr, after exposure to insults that are relevant to the pathogenesis of human CLD, and to simultaneously seek therapies to down regulate this process. We propose to 1) determine LPS-evoked kinetics of myeloid cell mobilization and cytokine production in mice without Abr and Bcr 2) investigate proinflammatory cytokine-induced gene expression involving Abr and Bcr in alveolar macrophages, including TGF-131 3) examine the role of the lung endothelium in the pulmonary injury seen in mice lacking Abr and Bcr 4) investigate if unresolved inflammation and CLD will develop in newborn mice lacking Abr and Bcr after exposure to mild hyperoxia and LPS 5) explore lentiviral and peptide strategies to terminate LPS-induced inflammation based on Abr, Bcr and Rac. Studies will be performed using primary alveolar macrophages, endothelial cells and null mutant mice. The data obtained from our experiments will provide insight into mechanisms that exist to resolve inflammation, which have never been explored. Moreover, new therapies for pulmonary inflammation will be tested. Because inflammation is a major upstream factor in the development of CLD, our studies directly relate to the Program Project's main theme of seeking to understand and ultimately cure CLD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL060231-10
Application #
7827982
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
2009-04-01
Project End
2010-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
10
Fiscal Year
2009
Total Cost
$316,557
Indirect Cost
Name
Children's Hospital of Los Angeles
Department
Type
DUNS #
052277936
City
Los Angeles
State
CA
Country
United States
Zip Code
90027
Buckley, Susan; Shi, Wei; Xu, Wei et al. (2015) Increased alveolar soluble annexin V promotes lung inflammation and fibrosis. Eur Respir J 46:1417-29
Xing, Yiming; Wang, Runming; Li, Changgong et al. (2015) PTEN regulates lung endodermal morphogenesis through MEK/ERK pathway. Dev Biol 408:56-65
Li, Changgong; Li, Aimin; Xing, Yiming et al. (2013) Apc deficiency alters pulmonary epithelial cell fate and inhibits Nkx2.1 via triggering TGF-beta signaling. Dev Biol 378:13-24
Gong, Dapeng; Fei, Fei; Lim, Min et al. (2013) Abr, a negative regulator of Rac, attenuates cockroach allergen-induced asthma in a mouse model. J Immunol 191:4514-20
Gong, Dapeng; Shi, Wei; Yi, Sun-ju et al. (2012) TGF? signaling plays a critical role in promoting alternative macrophage activation. BMC Immunol 13:31
El-Hashash, Ahmed H K; Turcatel, Gianluca; Varma, Saaket et al. (2012) Eya1 protein phosphatase regulates tight junction formation in lung distal epithelium. J Cell Sci 125:4036-48
Xu, Pinglong; Liu, Jianming; Derynck, Rik (2012) Post-translational regulation of TGF-* receptor and Smad signaling. FEBS Lett 586:1871-84
Tiozzo, Caterina; Danopoulos, Soula; Lavarreda-Pearce, Maria et al. (2012) Embryonic epithelial Pten deletion through Nkx2.1-cre leads to thyroid tumorigenesis in a strain-dependent manner. Endocr Relat Cancer 19:111-122
Lamouille, Samy; Connolly, Erin; Smyth, James W et al. (2012) TGF-?-induced activation of mTOR complex 2 drives epithelial-mesenchymal transition and cell invasion. J Cell Sci 125:1259-73
Xu, Pinglong; Liu, Jianming; Sakaki-Yumoto, Masayo et al. (2012) TACE activation by MAPK-mediated regulation of cell surface dimerization and TIMP3 association. Sci Signal 5:ra34

Showing the most recent 10 out of 126 publications