The purpose of this proposal is to foster the scientific development and laboratory skills of Dr. Ivan Rosas in order that the candidate may become an independent investigator. The Pulmonary, Allergy and Critical Care Medicine Division at the University of Pittsburgh and it's Simmons Interstitial Lung Disease Center will provide the candidate with the ideal setting in which to test the hypothesis that clinical disease progression in IPF patients is associated with increases in Syndecan-2 expression and shedding. In order to identify candidate genes involved in the progression of IPF, the candidate performed microarray and targeted proteomic analysis of alveolar macrophages, broncho-alveolar lavage (BAL) and peripheral blood of IPF patients. He analyzed gene expression patterns in alveolar macrophages, and found that Syndecan-2 was upregulated. More importantly, the upregulation of Syndecan-2 correlated with disease severity in the study cohort. Syndecan-2, a member of the syndecan family of heparan-sulfate proteoglycans, can bind multiple chemokines, cytokines, growth factors and extracellular matrix proteins. Syndecan-2 can bind to these molecules as a membrane bound or shed protein. Although little is known about shedding and regulation of syndecans in human lung disease, they are known targets for matrix metallo-proteases (MMP's), which are highly abundant in the lungs of patients with IPF.
The specific aims of this proposal are: 1 To determine whether SDC2 levels are indicative and predictive of disease development and progression. 2.To determine what MMP's, increased in IPF, regulate Syndecan-2 shedding. 3.To determine the effects of syndecan expression and shedding on chemokine and growth factor bioavailability. The proposed research will offer insight into the role of Syndecan-2 in IPF disease progression. The knowledge obtained during the period of support will be the foundation for future studies determining the therapeutic potential of modulating levels of MMP's and heparan-sulfate proteoglycans in patients with IPF. Through the collaboration with Dr. Kaminski, Dr. Choi and a network of experienced researchers, the candidate will obtain the foundation for the development of an independent academic career.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23HL087030-05
Application #
8265924
Study Section
Special Emphasis Panel (ZHL1-CSR-R (O1))
Program Officer
Colombini-Hatch, Sandra
Project Start
2008-05-04
Project End
2013-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
5
Fiscal Year
2012
Total Cost
$151,881
Indirect Cost
$11,206
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Doyle, Tracy J; Lee, Joyce S; Dellaripa, Paul F et al. (2014) A roadmap to promote clinical and translational research in rheumatoid arthritis-associated interstitial lung disease. Chest 145:454-63
Morse, Danielle; Rosas, Ivan O (2014) Tobacco smoke-induced lung fibrosis and emphysema. Annu Rev Physiol 76:493-513
Mihalek, Andrew D; Rosas, Ivan O; Padera Jr, Robert F et al. (2013) Interstitial pneumonitis and the risk of chronic allograft rejection in lung transplant recipients. Chest 143:1430-5
Shi, Yuanyuan; Gochuico, Bernadette R; Yu, Guoying et al. (2013) Syndecan-2 exerts antifibrotic effects by promoting caveolin-1-mediated transforming growth factor-* receptor I internalization and inhibiting transforming growth factor-*1 signaling. Am J Respir Crit Care Med 188:831-41
Doyle, Tracy J; Hunninghake, Gary M; Rosas, Ivan O (2012) Subclinical interstitial lung disease: why you should care. Am J Respir Crit Care Med 185:1147-53
Doyle, Tracy J; Washko, George R; Fernandez, Isis E et al. (2012) Interstitial lung abnormalities and reduced exercise capacity. Am J Respir Crit Care Med 185:756-62
Xu, Jin-Fu; Washko, George R; Nakahira, Kiichi et al. (2012) Statins and pulmonary fibrosis: the potential role of NLRP3 inflammasome activation. Am J Respir Crit Care Med 185:547-56
Rosas, Ivan O; Yao, Jianhua; Avila, Nilo A et al. (2011) Automated quantification of high-resolution CT scan findings in individuals at risk for pulmonary fibrosis. Chest 140:1590-7
Washko, George R; Hunninghake, Gary M; Fernandez, Isis E et al. (2011) Lung volumes and emphysema in smokers with interstitial lung abnormalities. N Engl J Med 364:897-906
Washko, George R; Lynch, David A; Matsuoka, Shin et al. (2010) Identification of early interstitial lung disease in smokers from the COPDGene Study. Acad Radiol 17:48-53

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