In this project we will focus on defining the process of elastolytic injury of pulmonary cells and their extracellular matrix. In particular, we aim to identify the function of heparan sulfate proteoglycans (HSPGs) as regulators of elastolysis and modulators of the cellular response to injury. In addition, we will investigate the consequences of elastase injury to the extracellular matrix on vascular endothelial growth factor (VEGF) storage, release, and activity. Our previous studies have implicated proteoglycans as central mediators of elastase damage to pulmonary cells and matrix. Specifically, we have shown that HSPGs modulate growth factor storage, release, and transport within the matrix;moreover, we have also found that elastase-generated HSPG fragments feed back to inhibit elastase and that elastase leads to increased nuclear HSPGs, reduced histone acetylation, reduced tropoelastin expression, and release of VEGF fragments. We plan to expand our studies to focus on the function of released fragments of HSPGs, the specific HSPGs, syndecans 1 and 4, and VEGF.
Our specific aims are to: 1) Identify the mechanisms and functional consequences of HSPG inhibition of elastase activity. 2) Define the mechanisms and functional consequences of elastase release of VEGF from pulmonary cells and matrix. 3) Determine the role of HSPGs in mediating the response of lung fibroblasts to elastase injury. We will use a combination of biochemical, molecular, and biophysical approaches in conjunction with cell culture and animal studies utilizing syndecan knock out mice to investigate the complex process of lung injury and repair. Ultimately, these studies will provide critical insight into the cascade of events initiated by elastolytic injury and the subsequent development of emphysema. Project Narrative: Chronic Obstructive Pulmonary Disease, which includes emphysema, is the fourth leading cause of death in the United States, accounting for more than 120,000 deaths in 2002. To develop effective therapies for this "quiet killer" a more complete understanding of the underlying cellular and molecular causes is required. In the present project, we propose to identify new critical components of how the lung responds, appropriately and inappropriately, to a specific type of injury (elastolysis) so that this information might provide insight toward the development of therapies that aim to assist lung repair and avoid disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL088572-05
Application #
8197390
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Postow, Lisa
Project Start
2007-12-01
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2013-11-30
Support Year
5
Fiscal Year
2012
Total Cost
$402,188
Indirect Cost
$154,688
Name
Boston University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Hubbard, Brant; Buczek-Thomas, Jo Ann; Nugent, Matthew A et al. (2014) Heparin-dependent regulation of fibronectin matrix conformation. Matrix Biol 34:124-31
Derricks, Kelsey E; Rich, Celeste B; Buczek-Thomas, Jo Ann et al. (2013) Ascorbate enhances elastin synthesis in 3D tissue-engineered pulmonary fibroblasts constructs. Tissue Cell 45:253-60
Nugent, M A; Zaia, J; Spencer, J L (2013) Heparan sulfate-protein binding specificity. Biochemistry (Mosc) 78:726-35
Bais, Manish V; Nugent, Matthew A; Stephens, Danielle N et al. (2012) Recombinant lysyl oxidase propeptide protein inhibits growth and promotes apoptosis of pre-existing murine breast cancer xenografts. PLoS One 7:e31188
Naimy, Hicham; Buczek-Thomas, Jo Ann; Nugent, Matthew A et al. (2011) Highly sulfated nonreducing end-derived heparan sulfate domains bind fibroblast growth factor-2 with high affinity and are enriched in biologically active fractions. J Biol Chem 286:19311-9
Forsten-Williams, Kimberly; Kurtagic, Elma; Nugent, Matthew A (2011) Complex receptor-ligand dynamics control the response of the VEGF system to protease injury. BMC Syst Biol 5:170
Spencer, Jean L; Bernanke, Joel A; Buczek-Thomas, Jo Ann et al. (2010) A computational approach for deciphering the organization of glycosaminoglycans. PLoS One 5:e9389
Guarnieri, Frank; Spencer, Jean L; Lucey, Edgar C et al. (2010) A human surfactant peptide-elastase inhibitor construct as a treatment for emphysema. Proc Natl Acad Sci U S A 107:10661-6
Kurtagic, Elma; Jedrychowski, Mark P; Nugent, Matthew A (2009) Neutrophil elastase cleaves VEGF to generate a VEGF fragment with altered activity. Am J Physiol Lung Cell Mol Physiol 296:L534-46
Ritter, Michael C; Jesudason, Rajiv; Majumdar, Arnab et al. (2009) A zipper network model of the failure mechanics of extracellular matrices. Proc Natl Acad Sci U S A 106:1081-6

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