Neovascularization is a key regulatory process in fetal growth and development, providing nutrients and oxygen to tissues. Alterations within this process can lead to vascular abnormalities and impaired tissue development. Although a great deal is known regarding the interaction of factors promoting growth and development of the pulmonary vasculature, nothing is known regarding the molecular mechanisms that may counteract these stimuli. Accordingly the overall goals of this proposal are to determine, at a molecular level for the first time, the role of one putative negative modulator of lung vascular growth. I chose to focus on Endothelial monocyte activating polypeptide (EMAP) II as a candidate negative modulator because we recently identified a novel role for this cytokine as an anti-angiogenic factor in tumor vascular development and I now have preliminary data indicating that it may play a key role in negatively modulating angiogenesis within the developing mouse lung. I hypothesize that EMAP II is an important negative- regulator in the physiologic development and neovascularization of the lung.
The specific aims of this project are: 1) To define the temporo- spatial expression of EMAP II in the embryonic mouse lung, 2) To determine the mechanism by which EMAP II inhibits lung vascular development, and 3) To determine the molecular basis by which EMAP II, an anti-angiogenic factor, inhibits vascular endothelial cell growth by analyzing the effect of exogenous EMAP II on cell proliferation, and cell cycle events. These proposed studies will determine whether EMPA II is an important negative regulator in lung development and neovascularization and will determine the effect of abrogation and overexpression. Based on this information, novel approaches to the clinical treatment of lung regeneration after ischemia-reperfusion injury, chronic lung damage and lung transplantation may be identified.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29HL060061-04
Application #
6389883
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Berberich, Mary Anne
Project Start
1998-05-01
Project End
2001-07-31
Budget Start
2001-05-01
Budget End
2001-07-31
Support Year
4
Fiscal Year
2001
Total Cost
$9,143
Indirect Cost
Name
Children's Hospital of Los Angeles
Department
Type
DUNS #
094878337
City
Los Angeles
State
CA
Country
United States
Zip Code
90027
Legan, Susan K; Lee, Daniel D; Schwarz, Margaret A (2017) ?5?1 integrin mediates pulmonary epithelial cyst formation. Dev Dyn 246:475-484
Yuan, Chujun; Yan, Lin; Solanki, Pallavi et al. (2015) Blockade of EMAP II protects cardiac function after chronic myocardial infarction by inducing angiogenesis. J Mol Cell Cardiol 79:224-31
Bennett, Katherine M; Afanador, Maria D; Lal, Charitharth V et al. (2013) Ephrin-B2 reverse signaling increases ?5?1 integrin-mediated fibronectin deposition and reduces distal lung compliance. Am J Respir Cell Mol Biol 49:680-7
Schwarz, Margaret A; Thornton, Janet; Xu, Haiming et al. (2012) Cell proliferation and migration are modulated by Cdk-1-phosphorylated endothelial-monocyte activating polypeptide II. PLoS One 7:e33101
Chen, Yao; Legan, Susan K; Mahan, Anne et al. (2012) Endothelial-monocyte activating polypeptide II disrupts alveolar epithelial type II to type I cell transdifferentiation. Respir Res 13:1
Schwarz, Margaret A; Zheng, Haihua; Legan, Susan et al. (2011) Lung self-assembly is modulated by tissue surface tensions. Am J Respir Cell Mol Biol 44:682-91
Yu, Shibin; Poe, Bryan; Schwarz, Margaret et al. (2010) Fetal and postnatal lung defects reveal a novel and required role for Fgf8 in lung development. Dev Biol 347:92-108
Schwarz, Margaret A; Caldwell, Lauren; Cafasso, Danielle et al. (2009) Emerging pulmonary vasculature lacks fate specification. Am J Physiol Lung Cell Mol Physiol 296:L71-81